Author: "ON/MCT" / Topic: 0303 health sciences - Searchworks@Jio Institute Digital Library Search Results

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94 results on '"ON/MCT"'

1. Subcellular Chemical Imaging: New Avenues in Cell Biology

Author: Pietro Benettoni, Benoit Gallet, Giulia Veronesi, Sylvain Bohic, Rémi Tucoulou, Johan Decelle, Matthias Schmidt, Peta L. Clode, Niculina Musat, Hryhoriy Stryhanyuk, Melissa K. Passarelli, Light Photosynthesis & Metabolism (Photosynthesis), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Groupe modélisation et chimie théorique (MCT ), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), European Synchrotron Radiation Facility (ESRF), Groupe Microscopie Electronique et Méthodes (IBS-MEM), Institut de biologie structurale (IBS - UMR 5075), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Helmholtz Centre for Environmental Research, Department of Isotope Biogeochemistry (UFZ), Laboratory for Biological Geochemistry, École Polytechnique Fédérale de Lausanne (EPFL), Synchrotron Radiation for Biomedicine = Rayonnement SynchroTROn pour la Recherche BiomédicalE (STROBE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre for Microscopy, Characterisation and Analysis (CMCA), The University of Western Australia (UWA), UWA School of Biological Sciences, Défi X-Life grant from CNRS, Landmark ESFRI project, ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-INBS-0002,EMBRC-France,CENTRE NATIONAL DE RESSOURCES BIOLOGIQUES MARINES(2010), Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), Groupe modélisation et chimie théorique (MCT), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Synchrotron Radiation for Biomedicine [Grenoble] (STROBE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), GON, Nathalie, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Infrastructures - CENTRE NATIONAL DE RESSOURCES BIOLOGIQUES MARINES - - EMBRC-France2010 - ANR-10-INBS-0002 - INBS - VALID, and Ecole Polytechnique Fédérale de Lausanne (EPFL)
Subjects: Chemical imaging, Elemental imaging, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Cells, elemental imaging, x-ray-fluorescence, Correlative microscopy, X-ray fluorescence, neurons, Computational biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, ion mass-spectrometry, Multimodal Imaging, localization, nanosims, 03 medical and health sciences, 0302 clinical medicine, Imaging, Three-Dimensional, Animals, Humans, correlative microscopy, chemical imaging, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, lateral resolution, 0303 health sciences, electron microscopy, Cell Biology, elements, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, speciation, reveals, SIMS, electron-microscopy, 030217 neurology & neurosurgery, Subcellular Fractions
Abstract: International audience; To better understand the physiology and acclimation capability of the cell, one of the great challenges of the future is to access the interior of a cell and unveil its chemical landscape (composition and distribution of elements and molecules). Chemical imaging has greatly improved in sensitivity and spatial resolution to visualize and quantify nutrients, metabolites, toxic elements, and drugs in single cells at the subcellular level. This review aims to present the current potential of these emerging imaging technologies and to guide biologists towards a strategy for interrogating biological processes at the nanoscale. We also describe various solutions to combine multiple imaging techniques in a correlative way and provide perspectives and future directions for integrative subcellular imaging across different disciplines
Published: 2020
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2. Synthesis and Biological Activities of Naturally Functionalized Polyamines: An Overview

Author: Jean Michel Brunel, Sophie Negrel, Transporteurs membranaires, chimioresistance et drug-design (TMCD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), and Brunel, Jean Michel
Subjects: Pharmacology, 0303 health sciences, Engineering, 030306 microbiology, Mechanism (biology), business.industry, Organic Chemistry, Computational biology, Biochemistry, 3. Good health, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Discovery, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Polyamines, Humans, Molecular Medicine, business, 030304 developmental biology
Abstract: Recently, extensive researches have emphasized the fact that polyamine conjugates are becoming important in all biological and medicinal fields. In this review, we will focus our attention on natural polyamines and highlight recent progress in both fundamental mechanism studies and interests in the development and application for the therapeutic use of polyamine derivatives.
Published: 2021
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3. Autophagy: a novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model

Author: Laurent Meijer, Gordon B. Mills, Khandan Keyomarsi, Donald H. Lambert, Laura A. Lambert, Na Qiao, Kelly K. Hunt, Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Program in integrative biology. Research Institute, The Hospital for sick children [Toronto] (SickKids), Unité de Chimie Pharmaceutique et Radiopharmacie (UCL-CMFA 7340), Université Catholique de Louvain = Catholic University of Louvain (UCL), School of Environmental Sciences [Norwich], University of East Anglia [Norwich] (UEA), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Biogéosciences [UMR 6282] [Dijon] (BGS), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Biogéosciences [Dijon] ( BGS ), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), The Hospital for Sick Children, Unité de Chimie Pharmaceutique et Radiopharmacie ( UCL-CMFA 7340 ), Université Catholique de Louvain ( UCL ), University of East Anglia [Norwich] ( UEA ), Molécules et cibles thérapeutiques ( MCT ), and Centre National de la Recherche Scientifique ( CNRS )
Subjects: Cancer Research, Cell cycle checkpoint, MESH : Antineoplastic Combined Chemotherapy Protocols, medicine.medical_treatment, Apoptosis, MESH : Models, Biological, Pharmacology, MESH: Drug Synergism, 0302 clinical medicine, MESH : Tumor Cells, Cultured, MESH : Cytotoxins, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, MESH : G2 Phase, MESH : Purines, Cytotoxicity, Tumor Stem Cell Assay, 0303 health sciences, Cytotoxins, MESH: Tumor Stem Cell Assay, Drug Synergism, Sarcoma, MESH: Purines, Cell cycle, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, 030220 oncology & carcinogenesis, MESH: Cytotoxins, medicine.drug, G2 Phase, MESH : Drug Synergism, MESH : Tumor Stem Cell Assay, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH : Sarcoma, Models, Biological, Article, 03 medical and health sciences, MESH: Doxorubicin, Therapeutic index, medicine, Autophagy, Roscovitine, MESH : Doxorubicin, MESH: Autophagy, Humans, Doxorubicin, MESH: Tumor Cells, Cultured, 030304 developmental biology, Chemotherapy, MESH: Humans, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Apoptosis, MESH : Humans, MESH: Models, Biological, MESH : Autophagy, MESH: G2 Phase, Purines, MESH: Sarcoma, MESH : Apoptosis
Abstract: Doxorubicin is a genotoxic chemotherapy agent used in treatment of a wide variety of cancers. Significant clinical side effects, including cardiac toxicity and myelosuppression, severely limit the therapeutic index of this commonly used agent and methods which improve doxorubicin efficacy could benefit many patients. Because doxorubicin cytotoxicity is cell cycle specific, the cell cycle is a rational target to enhance its efficacy. We examined the direct, cyclin-dependent kinase inhibitor roscovitine as a means of enhancing doxorubicin cytotoxicity. This study showed synergistic cytotoxicity between doxorubicin and roscovitine in three sarcoma cell lines: SW-982 (synovial sarcoma), U2OS-LC3-GFP (osteosarcoma), and SK-LMS-1 (uterine leiomyosarcoma), but not the fibroblast cell line WI38. The combined treatment of doxorubicin and roscovitine was associated with a prolonged G2-M cell cycle arrest in the three sarcoma cell lines. Using three different methods for detecting apoptosis, our results revealed that apoptotic cell death did not account for the synergistic cytotoxicity between doxorubicin and roscovitine. However, morphologic changes observed by light microscopy and increased cytoplasmic LC3-GFP puncta in U20S-LC3-GFP cells after the combined treatment suggested the induction of autophagy. Induction of autophagy was also shown in SW-982 and SK-LMS-1 cells treated with both doxorubicin and roscovitine by acridine orange staining. These results suggest a novel role of autophagy in the enhanced cytotoxicity by cell cycle inhibition after genotoxic injury in tumor cells. Further investigation of this enhanced cytotoxicity as a treatment strategy for sarcomas is warranted. [Cancer Res 2008;68(19):7966–74]
Published: 2008
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4. Synthesis of new dipyrrolo- and furopyrrolopyrazinones related to tripentones and their biological evaluation as potential kinases (CDKs1-5, GSK-3) inhibitors

Author: Ronan Bureau, Christophe Rochais, Jana Sopkova‐de Oliveira Santos, Elodie Lescot, Laurent Meijer, Sylvain Rault, Patrick Dallemagne, Nghia Vu Duc, Laboratoire pour l'utilisation du rayonnement électromagnétique (LURE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-MENRT-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Evolution, Génomes et Spéciation (LEGS), Centre National de la Recherche Scientifique (CNRS), Laboratoire pour l'utilisation du rayonnement électromagnétique ( LURE ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -MENRT-Centre National de la Recherche Scientifique ( CNRS ), Centre d'Etudes et de Recherche sur le Médicament de Normandie ( CERMN ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Molécules et cibles thérapeutiques ( MCT ), Centre National de la Recherche Scientifique ( CNRS ), and Laboratoire Evolution, Génomes et Spéciation ( LEGS )
Subjects: Models, Molecular, Molecular model, Stereochemistry, 01 natural sciences, Chemical synthesis, 03 medical and health sciences, Glycogen Synthase Kinase 3, Structure-Activity Relationship, Cyclin-dependent kinase, Drug Discovery, Oximes, Structure–activity relationship, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Kinase Inhibitors, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Kinase, Organic Chemistry, General Medicine, Ketones, Combinatorial chemistry, In vitro, Cyclin-Dependent Kinases, 0104 chemical sciences, Cyclization, Pyrazines, biology.protein, Tau-protein kinase, Curtius rearrangement
Abstract: We herein describe the synthesis of novel dipyrrolo- and furopyrrolopyrazinones related to highly cytotoxic tripentones and to their oximes. The synthetic pathway involved in particular a Curtius rearrangement and a subsequent cyclisation into the title pyrazinones. The biological evaluation towards various cyclin-dependent kinases (CDKs1-5, GSK-3) highlighted a weak inhibitory activity for the oximes whose SAR was studied by a molecular modeling study.
Published: 2008
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5. Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin complex

Author: Olivier Lozach, Annie Valette, Laurent Meijer, Monique Clément, François Liger, Aude Echalier, Yoan Ferandin, Karima Bettayeb, Jonathan C. Morris, Bernard Marquet, Jane A. Endicott, Benoît Joseph, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre d'études et de recherches appliquées à la gestion (CERAG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Centre National de la Recherche Scientifique (CNRS), Institut de Mathématiques (UNINE), Université de Neuchâtel (UNINE), Centre de recherche en gestion (CRG), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Molécules et cibles thérapeutiques ( MCT ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'économie et de sociologie du travail ( LEST ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie cellulaire et moléculaire du contrôle de la prolifération ( BCMCP ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'études et de recherches appliquées à la gestion ( CERAG ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Mathématiques ( UNINE ), Université de Neuchâtel, Centre de recherche en gestion ( CRG ), École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires ( ICBMS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'économie et de sociologie du travail (LEST), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, MESH : Cell Line, Indoles, DYRK1A, Cyclin A, MESH : Pyrimidines, MESH: Spheroids, Cellular, Apoptosis, Crystallography, X-Ray, 01 natural sciences, MESH: Bicyclo Compounds, Heterocyclic, MESH : Bicyclo Compounds, Heterocyclic, MESH: Structure-Activity Relationship, MESH : Indoles, Drug Discovery, MESH : Structure-Activity Relationship, MESH : Cyclin A, MESH: Crystallization, MESH: Indoles, 0303 health sciences, MESH : Cell Survival, biology, Chemistry, Kinase, MESH : Drug Screening Assays, Antitumor, MESH: Drug Screening Assays, Antitumor, MESH : Cyclin-Dependent Kinase 2, 3. Good health, MESH : Antineoplastic Agents, MESH : Cyclin-Dependent Kinase 9, Biochemistry, MESH: Cell Survival, MESH : Crystallization, Molecular Medicine, Crystallization, MESH: Models, Molecular, MESH: Cell Line, Tumor, Cell Survival, MESH : Models, Molecular, MESH: Cyclin-Dependent Kinase 2, Antineoplastic Agents, MESH: Cyclin-Dependent Kinase 9, Cell Line, Structure-Activity Relationship, 03 medical and health sciences, Cyclin-dependent kinase, Cell Line, Tumor, Spheroids, Cellular, Humans, Structure–activity relationship, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Aza Compounds, MESH: Humans, 010405 organic chemistry, MESH : Cell Line, Tumor, MESH: Apoptosis, Cyclin-Dependent Kinase 2, Cyclin-dependent kinase 2, MESH : Humans, MESH: Cyclin A, Bridged Bicyclo Compounds, Heterocyclic, MESH: Crystallography, X-Ray, Cyclin-Dependent Kinase 9, In vitro, 0104 chemical sciences, MESH: Cell Line, Pyrimidines, MESH: Aza Compounds, MESH: Pyrimidines, biology.protein, MESH : Spheroids, Cellular, MESH: Antineoplastic Agents, Cyclin-dependent kinase 9, Drug Screening Assays, Antitumor, MESH : Aza Compounds, MESH : Crystallography, X-Ray, MESH : Apoptosis
Abstract: We report the synthesis and biological characterization of 3-(pyrimidin-4-yl)-7-azaindoles (meriolins), a chemical hybrid between the natural products meridianins and variolins, derived from marine organisms. Meriolins display potent inhibitory activities toward cyclin-dependent kinases (CDKs) and, to a lesser extent, other kinases (GSK-3, DYRK1A). The crystal structures of 1e (meriolin 5) and variolin B (Bettayeb, K.; Tirado, O. M.; Marionneau-Lambert, S.; Ferandin, Y.; Lozach, O.; Morris, J.; Mateo-Lozano, S.; Drückes, P.; Schächtele, C.; Kubbutat, M.; Liger, F.; Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario, V.; Meijer, L. Cancer Res. 2007, 67, 8325-8334) in complex with CDK2/cyclin A reveal that the two inhibitors are orientated in very different ways inside the ATP-binding pocket of the kinase. A structure-activity relationship provides further insight into the molecular mechanism of action of this family of kinase inhibitors. Meriolins are also potent antiproliferative and proapoptotic agents in cells cultured either as monolayers or in spheroids. Proapoptotic efficacy of meriolins correlates best with their CDK2 and CDK9 inhibitory activity. Meriolins thus constitute a promising class of pharmacological agents to be further evaluated against the numerous human diseases that imply abnormal regulation of CDKs including cancers, neurodegenerative disorders, and polycystic kidney disease.
Published: 2008
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6. Nuclear translocation of silver ions and hepatocyte nuclear receptor impairment upon exposure to silver nanoparticles

Author: Mireille Chevallet, Christine Moriscot, Isabelle Michaud-Soret, Benoit Gallet, Giulia Veronesi, Peggy Charbonnier, Wojciech Bal, Cécile Cottet-Rousselle, Aurélien Deniaud, Rémi Tucoulou, Vanessa Tardillo Suárez, Elizaveta Karepina, Alexandra Fuchs, Pierre-Henri Jouneau, European Synchrotron Radiation Facility (ESRF), Biologie des Métaux (BioMet ), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Groupe Microscopie Electronique et Méthodes (IBS-MEM), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Integrated Structural Biology Grenoble (ISBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institute of Biochemistry and Biophysics, Polish Academy of Sciences, INSERM, U1160, Département de Gastroentérologie, Université Paris Diderot - Paris 7 (UPD7), Groupe modélisation et chimie théorique (MCT ), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), and Integrated Structural Biology Grenoble (ISBG - UMS 3518 )
Subjects: [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, 0303 health sciences, Chemistry, Nucleolus, Materials Science (miscellaneous), 02 engineering and technology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 021001 nanoscience & nanotechnology, Silver nanoparticle, Nuclear translocation, 03 medical and health sciences, Subcellular distribution, Human health, medicine.anatomical_structure, Nuclear receptor, Hepatocyte, [SDE]Environmental Sciences, medicine, Biophysics, 0210 nano-technology, Intracellular, 030304 developmental biology, General Environmental Science
Abstract: International audience; The impact on human health of long-term exposure to low doses of silver nanoparticles (AgNPs) remainsunderstudied. Cellular studies have shown the intracellular dissolution of AgNPs within endolysosomesfollowed by Ag(I) binding to biomolecular thiolate-containing molecules. However, the precise subcellulardistribution of Ag(I) and the nature of the disrupted physiological pathways remained unknown. Novelimaging approaches enabled us to visualize the trafficking of AgNP-containing lysosomes towards aperinuclear location and a nuclear transfer of Ag(I) species with accumulation in the nucleoli. These Ag(I)species impaired nuclear receptor activity, disrupting critical mechanisms of liver physiology in low doseexposure scenarios, thus justifying further research into defining a framework for the safe use of AgNPs.
Published: 2020
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7. The transposable element-rich genome of the cereal pest Sitophilus oryzae

Author: Arian F.A. Smit, Séverine Balmand, Stefano Colella, Nicolas Montagné, Amparo Latorre, Jessica M. Storer, Nelly Burlet, Jeb Rosen, Caroline Blanc, Federica Calevro, Marina Marcet-Houben, Marie-France Sagot, Patrick Callaerts, Waël Zamoum, Patrice Baa-Puyoulet, Anna Zaidman-Rémy, Clément Goubert, Rita Rebollo, Louis Beranger, Carlos Vargas-Chávez, Gautier Richard, Ana Tereza Ribeiro de Vasconcelos, Justin Maire, Agnès Vallier, Elisa Dell’Aglio, Florent Masson, Robert Hubley, Sandrine Hughes, Camille Meslin, Gérard Febvay, Aurélien Vigneron, Nicolas Parisot, Théo Chancy, Cristina Vieira, Abdelaziz Heddi, Alex Di Genova, Benjamin Gillet, André Da Silva Barbosa, Carole Vincent-Monégat, Emmanuelle Jacquin-Joly, Hubert Charles, Mariana Galvão Ferrarini, Matthieu Boulesteix, Toni Gabaldón, Alexandra L. Gerber, Andrés Moya, Aymeric Bonnamour, Biologie Fonctionnelle, Insectes et Interactions (BF2I), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratorio Nacional de Computação Cientifica [Rio de Janeiro] (LNCC / MCT), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institute for Systems Biology [Seattle] (ISB), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana [Espagne] (FISABIO), Institut de Génétique, Environnement et Protection des Plantes (IGEPP), Université de Rennes (UR)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Eléments transposables, évolution, populations, Département génétique, interactions et évolution des génomes [LBBE] (GINSENG), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Institut d'écologie et des sciences de l'environnement de Paris (iEES Paris ), Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Rennes (UR)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Rennes Angers, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Région Auvergne-Rhône-Alpes, European Regional Development Fund, PGC2018-099344-B-I00, Ministerio de Ciencia, Innovación y Universidades, PROMETEO/2018/133, Conselleria d’Educació, Generalitat Valenciana, Institut National des Sciences Appliquées de Lyon, ANR-10-BLAN-1701, Agence Nationale de la Recherche, IDEX-Lyon PALSE IMPULSION, Ministerio de Economía y Competitividad, ANR-17-CE20-0031,GREEN,Comprendre les mécanismes de régulation et la fonction des gènes de la réponse immunitaire de l'hôte pour perturber la symbiose et le contrôle des endosymbiotes chez les insectes nuisibles(2017), ANR-17-CE20-0015,Unleash,Découverte de la relation entre épigénétique et symbiose chez l'insecte(2017), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Barcelona Supercomputing Center, Agence Nationale de la Recherche (France), European Commission, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat Valenciana, and Ministerio de Economía y Competitividad (España)
Subjects: Life Sciences & Biomedicine - Other Topics, Weevil, ALPHA-AMYLASE INHIBITORS, Physiology, Cell Communication, Plant Science, drosophila immune-response, Genome, HORIZONTAL GENE-TRANSFER, MULTIPLE SEQUENCE ALIGNMENT, 0302 clinical medicine, Structural Biology, Biology (General), Sitophilus oryzae Genome, 2. Zero hunger, Genetics, 0303 health sciences, Endosymbiosis Immunity, biology, Endosymbiosis, horizontal gene-transfer, Sitophilus, Sitophilus oryzae, food and beverages, wide analysis, Coleoptera, RED FLOUR BEETLE, Horizontal gene transfer, multiple sequence alignment, Agricultural pests, stored-product insects, phosphine resistance, General Agricultural and Biological Sciences, Life Sciences & Biomedicine, Research Article, DIGESTIVE PROTEINASES, Biotechnology, Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC], Transposable element, Sodalis, food.ingredient, QH301-705.5, PRIMARY ENDOSYMBIONT, Evolution, alpha-amylase inhibitors, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Rice weevil, food, STORED-PRODUCT INSECTS, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], PHOSPHINE RESISTANCE, Animals, Humans, DROSOPHILA IMMUNE-RESPONSE, Red flour beetle, Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Science & Technology, Immunity, Cell Biology, primary endosymbiont, biology.organism_classification, digestive proteinases, Genòmica, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, red flour beetle, DNA Transposable Elements, Weevils, Edible Grain, WIDE ANALYSIS, Transposable elements, 030217 neurology & neurosurgery, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis, Developmental Biology
Abstract: Parisot et al., [Background]: The rice weevil Sitophilus oryzae is one of the most important agricultural pests, causing extensive damage to cereal in fields and to stored grains. S. oryzae has an intracellular symbiotic relationship (endosymbiosis) with the Gram-negative bacterium Sodalis pierantonius and is a valuable model to decipher host-symbiont molecular interactions., [Results]: We sequenced the Sitophilus oryzae genome using a combination of short and long reads to produce the best assembly for a Curculionidae species to date. We show that S. oryzae has undergone successive bursts of transposable element (TE) amplification, representing 72% of the genome. In addition, we show that many TE families are transcriptionally active, and changes in their expression are associated with insect endosymbiotic state. S. oryzae has undergone a high gene expansion rate, when compared to other beetles. Reconstruction of host-symbiont metabolic networks revealed that, despite its recent association with cereal weevils (30 kyear), S. pierantonius relies on the host for several amino acids and nucleotides to survive and to produce vitamins and essential amino acids required for insect development and cuticle biosynthesis., [Conclusions]: Here we present the genome of an agricultural pest beetle, which may act as a foundation for pest control. In addition, S. oryzae may be a useful model for endosymbiosis, and studying TE evolution and regulation, along with the impact of TEs on eukaryotic genomes., Funding for this project was provided by the Fondation de l’Institut National des Sciences Appliquées-Lyon (INSA-Lyon), the research direction of INSA-Lyon, the Santé des Plantes et Environnement (SPE) department at the Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), the French ANR-10-BLAN-1701 (ImmunSymbArt), the French ANR-13-BSV7-0016-01 (IMetSym), the French ANR-17_CE20_0031_01 (GREEN), and a grant from la Région Rhône-Alpes (France) to AH. RR received funding from the French ANR-17-CE20-0015 (UNLEASH) and the IDEX-Lyon PALSE IMPULSION initiative. The project was also funded by European Regional Development Fund (ERDF) and Ministerio de Ciencia, Innovación y Universidades (Spain) PGC2018-099344-B-I00 to AL, and PID2019-105969GB-I00 to AM and Conselleria d’Educació, Generalitat Valenciana (Spain), grant number PROMETEO/2018/133 to AM. CV-C was a recipient of a fellowship from the Ministerio de Economía y Competitividad (Spain) and a grant from la Région Rhône-Alpes (France).
Published: 2021
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8. Live single-cell transcriptional dynamics via RNA labelling during the phosphate response in plants

Author: Edouard Bertrand, Nathalie Pochon, Eric Maréchal, Sahar Hani, James Whelan, Rémy Merret, Marie-Christine Thibaud, Laura Cuyas, Pascale David, Laurent Nussaume, Orestis Faklaris, Hélène Javot, David Secco, Florian Mueller, Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Signalisation de l'Adaptation des Végétaux à l'Environnement (SAVE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Department of Animal Plant and Soil Sciences, La Trobe Institute for Agriculture and Food (LIAF), La Trobe University-La Trobe University, Laboratoire Génome et développement des plantes (LGDP), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Biologie végétale et microbiologie environnementale - UMR7265 (BVME), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Centre Mondial de l'Innovation Roullier, Groupe Roullier, La Trobe University [Melbourne], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), LIPID, Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Plant Environmental Physiology and Stress Signaling (PEPSS), S.H. was supported by a PhD fellowship from the CEA and PACA region, ANR Reglisse 13-906 ADAP-008 fellowship and CEA DRF impulsion program with FOSSI project supported EM, LC, LN, MCT, PD. Additional grant support were also received by HJ from CEA-Enhanced Eurotalent and ANR PhlowZ 19-CE-13-0007.We acknowledge the MRI imaging facility (belonging to the National Infrastructure France-BioImaging supported by the French National Research Agency, ANR-10-INBS-04),and the ZoOM platform (supported by the Région Provence Alpes Côte d’Azur, the Conseil General of Bouches du Rhône, the French Ministry of Research, the Centre National de la Recherche Scientifique and the Commissariat à l’Energie Atomique et aux Energies Alternatives)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0041,TULIP,Towards a Unified theory of biotic Interactions: the roLe of environmental(2010), ANR-13-ADAP-0008,Reglisse,Régulation de l'interconversion des glycérolipides chez les plantes en réponse aux variations environnementales(2013), and ANR-19-CE13-0007,PHLOWZ,Approche systémique de l'interaction entre les voies de signalisation du Zinc et du Phosphate(2019)
Subjects: 0106 biological sciences, Transcription, Genetic, [SDV]Life Sciences [q-bio], Cell, Arabidopsis, RNA polymerase II, Plant Science, 01 natural sciences, Phosphates, 03 medical and health sciences, Gene Expression Regulation, Plant, Stress, Physiological, Plant Cells, medicine, Transcriptional regulation, Allele, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, RNA, biology.organism_classification, Cell biology, Kinetics, medicine.anatomical_structure, biology.protein, RNA Polymerase II, Steady state (chemistry), 010606 plant biology & botany
Abstract: International audience; Plants are constantly adapting to ambient fluctuations through spatial and temporal transcriptional responses. Here, we implemented the latest-generation RNA imaging system and combined it with microfluidics to visualize transcriptional regulation in living Arabidopsis plants. This enabled quantitative measurements of the transcriptional activity of single loci in single cells, in real time and under changing environmental conditions. Using phosphate-responsive genes as a model, we found that active genes displayed high transcription initiation rates (one initiation event every ~3 s) and frequently clustered together in endoreplicated cells. We observed gene bursting and large allelic differences in single cells, revealing that at steady state, intrinsic noise dominated extrinsic variations. Moreover, we established that transcriptional repression triggered in roots by phosphate, a crucial macronutrient limiting plant development, occurred with unexpectedly fast kinetics (on the order of minutes) and striking heterogeneity between neighbouring cells. Access to single-cell RNA polymerase II dynamics in live plants will benefit future studies of signalling processes.
Published: 2021
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9. Modification of outer membrane permeability and alteration of LPS in veterinary enterotoxigenic Escherichia coli

Author: Véronique Guerin-Faublée, Jean-Marie Pagès, Anne Davin-Regli, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), rosa, emmanuelle, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: Diarrhea, Lipopolysaccharides, LPS, Membrane permeability, Antibiotic resistance, medicine.drug_class, [SDV]Life Sciences [q-bio], Polymyxin, Cattle Diseases, Porins, Microbial Sensitivity Tests, medicine.disease_cause, Permeability, Microbiology, 03 medical and health sciences, Drug Resistance, Multiple, Bacterial, Enterotoxigenic Escherichia coli, medicine, Animals, Polymyxins, Escherichia coli Infections, 030304 developmental biology, 0303 health sciences, Membranes, General Veterinary, ETEC, 030306 microbiology, Chemistry, Anti-Bacterial Agents, 3. Good health, [SDV] Life Sciences [q-bio], Dairying, Chloramphenicol, Porin, Colistin, bacteria, Cattle, Efflux, Bacterial outer membrane, Polymyxin B, Fluoroquinolones, medicine.drug
Abstract: International audience; Enterotoxigenic Escherichia coli (ETEC) is a worrying cause of diarrhoea in calves and the drug multiresistance phenotype concerning various antibiotic families are of concern. Resistance mechanisms associated with envelope changes (porin expression, efflux pump overexpression, lipolysaccahride (LPS) modification) were studied in 14 ETEC isolates selected for their resistance. We performed determinations of (i) antimicrobials Minimal Inhibitory Concentrations with or without the efflux pump inhibitor phenylalanine arginine β-naphthylamide; (ii) colistin and polymyxin MICs with and without EDTA, (iii) intracellular accumulation of chloramphenicol in presence of an energy uncoupler of pump energy, (iv) and immunodetection of porins and evaluation of porin trimers thermostability.Results indicated that 9 strains presented significant efflux mechanisms overexpression, among them 8 were resistant to colistin and polymyxin B due to a modification of LPS structure as evidenced by EDTA effect and silver staining electrophoresis. The high resistant strains to colistin and polymyxin exhibited identical LPS patterns. Studies of E. coli porins indicated that the majority of strains didn't show modification in their amount, however analysis of porin thermostability showed that porin trimers of some resistant strains were relatively heat-labile, suggesting a misassembly of the functional trimer. The multidrug resistance (MDR) phenotypes detected in these selected ETEC corresponded to association of LPS modifications, abordive assembly of porin trimers and active efflux which drastically alter the antibiotic activity currently used to combat enteric infections caused by this pathogen.
Published: 2019
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10. The Polyaminoisoprenyl Potentiator NV716 Revives Old Disused Antibiotics against Intracellular Forms of Infection by Pseudomonas aeruginosa

Author: Brunel, Jean Michel, Wang, Gang, Brunel, Jean-Michel, Bolla, Jean-Michel, Van Bambeke, Françoise, Transporteurs membranaires, chimioresistance et drug-design (TMCD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences [Beijing] (CAS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Pharmacologie Cellulaire et Moléculaire [Brussels], Louvain Drug Research Institute [Bruxelles, Belgique] (LDRI), Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), Brunel, Jean Michel, UCL - SSS/LDRI - Louvain Drug Research Institute, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: medicine.drug_class, Antibiotics, Microbial Sensitivity Tests, medicine.disease_cause, Microbiology, 03 medical and health sciences, Ciprofloxacin, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, antibiotic, Drug Resistance, Multiple, Bacterial, medicine, Extracellular, Pharmacology (medical), efflux inhibitor, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, 030306 microbiology, Chemistry, Pseudomonas aeruginosa, intracellular bacteria, Chloramphenicol, biology.organism_classification, drug efflux, Anti-Bacterial Agents, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Efflux, Bacteria, Intracellular, medicine.drug
Abstract: Active efflux confers intrinsic resistance to multiple antibiotics in Pseudomonas aeruginosa, including old disused molecules. Beside resistance, intracellular survival is another reason for failure to eradicate bacteria with antibiotics. We evaluated the capacity of polyaminoisoprenyl potentiators (designed as efflux pump inhibitors [EPIs]) NV716 and NV731 compared to PAβN to restore the activity of disused antibiotics (doxycycline, chloramphenicol [substrates for efflux], and rifampin [nonsubstrate]) in comparison with ciprofloxacin against intracellular P. aeruginosa (strains with variable efflux levels) in THP-1 monocytes exposed over 24 h to antibiotics alone (0.003 to 100× MIC) or combined with EPIs. Pharmacodynamic parameters (apparent static concentrations [C(s)] and maximal relative efficacy [E(max)]) were calculated using the Hill equation of concentration-response curves. PAβN and NV731 moderately reduced (0 to 4 doubling dilutions) antibiotic MICs but did not affect their intracellular activity. NV716 markedly reduced (1 to 16 doubling dilutions) the MIC of all antibiotics (substrates or not for efflux; strains expressing efflux or not); it also improved their relative potency and maximal efficacy (i.e., lower C(s); more negative E(max)) intracellularly. In parallel, NV716 reduced the persister fraction in stationary cultures when combined with ciprofloxacin. In contrast to PAβN and NV731, which act only as EPIs against extracellular bacteria, NV716 can resensitize P. aeruginosa to antibiotics whether they are substrates or not for efflux, both extracellularly and intracellularly. This suggests a complex mode of action that goes beyond a simple inhibition of efflux to reduce bacterial persistence. NV716 appears to be a useful adjuvant, including to disused antibiotics with low antipseudomonal activity, to improve their activity, including against intracellular P. aeruginosa.
Published: 2021
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11. Docosahexaenoic fatty acid-containing phospholipids affect plasma membrane susceptibility to disruption by bacterial toxin-induced macroapertures

Author: Frank Lafont, Jean-Christophe Olivo-Marin, Delphine Debayle, Amel Mettouchi, Emmanuel Lemichez, Lucile Fleuriot, David Gonzalez-Rodriguez, Meng-Chen Tsai, Bruno Antonny, Stephane Dallongeville, Camille Morel, Hélène Barelli, Sébastien Janel, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Toxines bactériennes - Bacterial Toxins, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Physique - Approche Multi-échelle des Milieux Complexes (LCP-A2MC), Université de Lorraine (UL), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Analyse d'images biologiques - Biological Image Analysis (BIA), This work was supported by a grant from the Fondation pour la Recherche Médicale (Convention DEQ20180339156 Equipes FRM 2018), the Agence Nationale de la Recherche (ANR-11-LABX-0028-01, ANR-15-CE18-0016,ANR10-EQPX-04-01, ANR-10-INBS-04, and ANR-10-LABX-62-IBEID) and FEDER 12,001,407. MCT was supported by a PhD fellowship from the Labex Signalife PhD Programme and by the Fondation pour la Recherche Médicale(Contrat FDT201904008135)., ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-15-CE18-0016,TransEndotheliaTunnel,Vers la prévention de dysfonctions vasculaires et la délivrance de médicaments au travers des endothelia(2015), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), DELARUE, NADINE, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Vers la prévention de dysfonctions vasculaires et la délivrance de médicaments au travers des endothelia - - TransEndotheliaTunnel2015 - ANR-15-CE18-0016 - AAPG2015 - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, and Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID
Subjects: RHOA, [SDV]Life Sciences [q-bio], Cell, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, medicine.disease_cause, Umbilical vein, 03 medical and health sciences, 0302 clinical medicine, medicine, Transcellular, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, Chemistry, Fatty acid, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Docosahexaenoic acid, biology.protein, lipids (amino acids, peptides, and proteins), 030217 neurology & neurosurgery, Exotoxin, Homeostasis
Abstract: Metabolic studies and animal knockout models point to the critical role of polyunsaturated docosahexaenoic acid (22:6, DHA)-containing phospholipids (PLs) in physiology. Here, we study the impact of DHA-PLs on the dynamics of transendothelial cell macroapertures (TEMs) tunnels triggered by the RhoA GTPase inhibitory exotoxin C3 from Clostridium botulinum. Through lipidomic analyses, we show that primary human umbilical vein endothelial cells (HUVECs) subjected to DHA-diet undergo a 6-fold DHA-PLs enrichment in plasma membrane at the expense of monounsaturated OA-PLs. In contrast, OA-diet had almost no effect on PLs composition. Consequently, DHA treatment increases the nucleation rate of TEMs by 2-fold that we ascribe to a reduction of cell thickness. We reveal that the global transcellular area of cells remains conserved through a reduction of the width and lifetime of TEMs. Altogether, we reveal a homeostasis between plasma membrane DHA-PLs content and large-scale membrane dynamics.
Published: 2021

12. Complete Genome Sequence of Strain SS-5, a Magnetotactic Gammaproteobacterium Isolated from the Salton Sea, a Shallow, Saline, Endorheic Rift Lake Located on the San Andreas Fault in California

Author: Ana Tereza Ribeiro de Vasconcelos, Dennis A. Bazylinski, Caroline L. Monteil, Corey Geurink, Denis Trubitsyn, Viviana Morillo-Lopez, Luiz Gonzaga Paula de Almeida, Christopher T. Lefèvre, Fernanda Abreu, Longwood University [Farmville], Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Nevada [Las Vegas] (WGU Nevada), Laboratorio Nacional de Computação Cientifica [Rio de Janeiro] (LNCC / MCT), Universidade Federal do Rio de Janeiro (UFRJ), ANR-18-CE31-0003,SIGMAG,SIGNATURE DES MAGNETITES PRODUITES PAR LES BACTERIES MAGNETOTACTIQUES : PERSPECTIVES CHIMIQUES ET ISOTOPIQUES(2018), ANR-19-CE01-0005,PHOSTORE,Piégeage du phosphore : contribution des bactéries magnétotactiques dans les zones de transition oxique-anoxique(2019), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Whole genome sequencing, 0303 health sciences, Rift, San andreas fault, Strain (chemistry), 030306 microbiology, Genome Sequences, Magnetosome, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 6. Clean water, 03 medical and health sciences, Paleontology, Immunology and Microbiology (miscellaneous), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Magnetotaxis, Molecular Biology, Geology, 030304 developmental biology, Biomineralization
Abstract: We report the 3.7-Mb genome sequence of strain SS-5, a magnetotactic, sulfur-oxidizing rod and member of the family Chromatiaceae of the class Gammaproteobacteria, which biomineralizes membrane-bounded, elongated, prismatic octahedral, magnetite nanocrystals. This genome sequence brings further diversity for understanding the origin and evolution of magnetotaxis and magnetosome biomineralization., We report the 3.7-Mb genome sequence of strain SS-5, a magnetotactic, sulfur-oxidizing rod and member of the family Chromatiaceae of the class Gammaproteobacteria, which biomineralizes membrane-bound, elongated, prismatic octahedral, magnetite nanocrystals. This genome sequence brings further diversity for understanding the origin and evolution of magnetotaxis and magnetosome biomineralization.
Published: 2021
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13. Virological failure and antiretroviral resistance among HIV-infected children after five years follow-up in the ANRS 12225-PEDIACAM cohort in Cameroon

Author: Mathurin Cyrille Tejiokem, Angeladine Kenne, Ida Calixte Penda, Francis Ateba Ndongo, Jules Brice Tchatchueng Mbougua, Francis Yuya Septoh, Suzie Tetang Ndiang, Josiane Warszawski, Albert Faye, Paul Alain Tagnouokam-Ngoupo, Sorel Jakpou, Jeannine Eboumbou Ngallè, Centre Pasteur du Cameroun, Réseau International des Instituts Pasteur (RIIP), Université de Douala, Centre Hospitalier Essos [Yaoundé, Cameroun], Hôpital Laquintinie [Douala, Cameroun], Fondation Chantal Biya (FCB), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and This prospective study is sponsored by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS), grants ANRS 12140 and 12225 to MCT.
Subjects: RNA viruses, Male, Pediatrics, [SDV]Life Sciences [q-bio], HIV Infections, Drug resistance, Pathology and Laboratory Medicine, Geographical Locations, Families, chemistry.chemical_compound, 0302 clinical medicine, Immunodeficiency Viruses, Interquartile range, Medicine and Health Sciences, Public and Occupational Health, Cameroon, Prospective Studies, Treatment Failure, 030212 general & internal medicine, Children, Virus Testing, 0303 health sciences, Multidisciplinary, Pharmaceutics, virus diseases, Lamivudine, Viral Load, Vaccination and Immunization, 3. Good health, Medical Microbiology, Viral Pathogens, Rilpivirine, Viruses, Cohort, Medicine, Drug Therapy, Combination, Female, Pathogens, HIV drug resistance, Research Article, Maternal Age, medicine.drug, Adult, medicine.medical_specialty, Nevirapine, Efavirenz, Anti-HIV Agents, Science, Immunology, Antiretroviral Therapy, Microbiology, 03 medical and health sciences, Antiviral Therapy, Drug Therapy, Diagnostic Medicine, Virology, Retroviruses, Drug Resistance, Viral, medicine, Humans, Microbial Pathogens, 030306 microbiology, business.industry, Lentivirus, Organisms, Biology and Life Sciences, HIV, Infant, Infectious Disease Transmission, Vertical, chemistry, Age Groups, People and Places, Africa, HIV-1, Population Groupings, Preventive Medicine, business, Viral Transmission and Infection, Follow-Up Studies
Abstract: Objective In the present study, we aimed to evaluate the virological failure (VF) and drug resistance among treated HIV-infected children after five years follow-up in the ANRS-Pediacam cohort in Cameroon. Methods From November 2007 to October 2011, HIV-infected children born to HIV-infected mothers were included in the ANRS-PEDIACAM study and followed-up for more than 5 years. Plasma viral load (VL) was measured at each visit (every three months until month 24 and every 6 months thereafter). VF was the main outcome and HIV drug resistance test was performed using the ANRS procedures and algorithm. Results Data from 155 children were analyzed. The median age at combination antiretroviral therapy (cART) initiation was 4.2 months (interquartile range (IQR): 3.2–5.8), with 103 (66.5%) children taking LPV/r-containing regimen and 51 (32.9%) children taking NVP. After five years follow-up, 63 (40.6%; CI: 32.9–48.8) children experienced VF. The median duration between cART initiation and VF was 22.1 months (IQR: 11.9–37.1) with a median VL of 4.8 log10 (IQR: 4.0–5.5). Among the 57 children with HIV drug resistance results, 40 (70.2%) had at least one drug resistance mutation. The highest resistance rates (30.4–66.1%) were obtained with Lamivudine; Efavirenz; Nevirapine and Rilpivirine. Conclusions These results show high resistance to NNRTI and emphasize the need of VL and resistance tests for optimal follow-up of HIV-infected people especially children.
Published: 2021
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14. Antibiotic adjuvants to rescue Pseudomonas aeruginosa from tetracycline antibiotics resistance

Author: Jean M. Brunel, Hana Douafer, Naouel Klibi, Azza Troudi, Jean-Michel Bolla, Brunel, Jean Michel, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Université de Tunis El Manar (UTM), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: Pharmacology, 0303 health sciences, 030306 microbiology, business.industry, medicine.drug_class, Pseudomonas aeruginosa, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Tetracycline antibiotics, Antibiotics, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, medicine.disease_cause, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Microbiology, 03 medical and health sciences, Infectious Diseases, Antibiotic adjuvants, Tetracycline antibiotic, Polyamines, Medicine, Polyaminoisoprenyl derivatives, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business, 030304 developmental biology
Abstract: Introduction: An attractive antibiotic-adjuvant strategy consisting of the design and synthesis of polyaminoisoprenyl molecules able to restore the antibiotic activity of tetracycline antibiotics against resistant Pseudomonas aeruginosa bacterial strains has been developed. Methods: These chemo-sensitizers are readily prepared from geraniol and farnesol in an efficient two steps synthesis with good to moderate yields varying from 38 to 64% and leading to a significant decrease in antibiotic resistance. Results: Thus, the influence of the nature of the tetracycline antibiotic used as well as the structure of the polyaminoisoprenyl derivatives involved in the outcome of the antibiotic-adjuvant combination against P. aeruginosa resistance to tetracyclines were investigated. Conclusion: Additionally, our data suggested that their mechanism of action is closely associated with the increase of the outer-membrane permeability.
Published: 2021
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15. Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation

Author: Jennifer Janina Stepanek, Abdulkadir Yayci, Martin Kozik, Niklas B.M. Janzing, Britta Schubert, Martin Benda, Yvonne Märtens, Kenneth C. Keiler, Jared T. Shaw, Lars I. Leichert, Bingyao Zhu, Tadeja Lukežič, Heike Brötz-Oesterhelt, Michaela Wenzel, Jörg Stülke, Maya Penkova, Ümran Ay, Kathi Scheinpflug, John N. Alumasa, Reece G. Miller, Christoph Helmut Rudi Senges, Christian Hertweck, Jean M. Brunel, Helen L. Warmuth, Sina Schäkermann, Julia E. Bandow, Nicole Lorenz, Melissa Vázquez Hernández, Bauke Albada, Nadja Raatschen, Jens Bongard, Nohemy A. Sorto, Pascal Prochnow, Nils Metzler-Nolte, Hrvoje Petković, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: Proteomics, Auranofin, Physiology, medicine.drug_class, Antibiotics, Chemical biology, Computational biology, Mechanism of action, Biology, Microbiology, 03 medical and health sciences, Bacterial Proteins, medicine, Pharmacology (medical), Mechanisms of Action: Physiological Effects, Repurposing, 030304 developmental biology, Pharmacology, 0303 health sciences, 030306 microbiology, Proteomic Profiling, Drug discovery, Antibiotic, Pharmacology and Pharmaceutical Sciences, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Anti-Bacterial Agents, 3. Good health, Infectious Diseases, 5.1 Pharmaceuticals, Medical Microbiology, Tetracyclines, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Development of treatments and therapeutic interventions, medicine.symptom, Infection, Biotechnology, Bacillus subtilis, medicine.drug
Abstract: New antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis., New antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. Comparison of proteomic responses (CoPR) allows the rapid identification of antibiotics with dual mechanisms of action as shown for atypical tetracyclines. It also aids in generating hypotheses on mechanisms of action as presented for salvarsan (arsphenamine) and the antirheumatic agent auranofin, which is under consideration for repurposing. Proteomic profiling also provides insights into the impact of antibiotics on bacterial physiology through analysis of marker proteins indicative of the impairment of cellular processes and structures. As demonstrated for trans-translation, a promising target not yet exploited clinically, proteomic profiling supports chemical biology approaches to investigating bacterial physiology.
Published: 2020
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16. New Polyaminoisoprenyl Antibiotics Enhancers against Two Multidrug-Resistant Gram-Negative Bacteria from Enterobacter and Salmonella Species

Author: Aurélie Lieutaud, Jean Michel Brunel, Jean Michel Bolla, Cyril Pieri, Transporteurs membranaires, chimioresistance et drug-design (TMCD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Brunel, Jean Michel, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), and rosa, emmanuelle
Subjects: Salmonella, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, 010402 general chemistry, Enterobacter aerogenes, medicine.disease_cause, 01 natural sciences, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Discovery, medicine, Cytotoxicity, Amination, ComputingMilieux_MISCELLANEOUS, Doxycycline, 0303 health sciences, Efflux pump, biology, 030306 microbiology, Chemistry, Enterobacter, biology.organism_classification, Combinatorial chemistry, 0104 chemical sciences, 3. Good health, [SDV] Life Sciences [q-bio], Multi-drug resistance, Gram-negative bacteria, Antibiotic enhancers, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Polyaminoisoprenyl derivatives, Molecular Medicine, Bacteria, medicine.drug
Abstract: International audience; A series consisting of new polyaminoisoprenyl derivatives were prepared in moderate to good chemical yields varying from 32 to 64% according two synthetic pathways: 1) using a titanium reductive amination reaction affording a 50/50 mixture of cis and trans isomers 2) a direct nucleophilic substitution leading to a stereoselective synthesis of the compounds of interest. These compounds were then successfully evaluated for their in vitro antibiotic enhancer properties against resistant Gram-negative bacteria of four antibiotics belonging to four different families. The mechanism of action against Enterobacter aerogenes of one of the most efficient of these chemosensitizing agents was precisely evaluated by using fluorescent dyes to measure outer-membrane permeability and to determine membrane depolarization. The weak cytotoxicity encountered led us to perform an in vivo experiment dealing with the treatment of mice infected with Salmonella Typhimurium and affording preliminary promising results in terms of tolerance and efficiency of the polyaminoisoprenyl derivative 5r / doxycycline combination.
Published: 2020
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17. Scope and limitations on aerosol drug delivery for the treatment of infectious respiratory diseases

Author: Jean Michel Brunel, Véronique Andrieu, Hana Douafer, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Transporteurs membranaires, chimioresistance et drug-design (TMCD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Brunel, Jean Michel
Subjects: Drug, medicine.medical_specialty, Side effect, medicine.drug_class, media_common.quotation_subject, Antibiotics, Pharmaceutical Science, 02 engineering and technology, 03 medical and health sciences, Drug Delivery Systems, Antibiotic resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Administration, Inhalation, medicine, Humans, Respiratory system, Intensive care medicine, Adverse effect, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, media_common, Aerosols, 0303 health sciences, business.industry, Bacterial Infections, 021001 nanoscience & nanotechnology, Anti-Bacterial Agents, 3. Good health, Review article, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 0210 nano-technology, business, Aerosol drug delivery
Abstract: The rise of antimicrobial resistance has created an urgent need for the development of new methods for antibiotics delivery to patients with pulmonary infections in order to mainly increase the effectiveness of the drugs administration, to minimize the risk of emergence of resistant strains, and to prevent patients reinfection. Since bacterial resistance is often related to antibiotic concentration, their pulmonary administration could eradicate strains resistant to the same drug at the concentration achieved through the systemic circulation. Pulmonary administration offers several advantages; it directly targets the site of the infection which allows the inhaled dose of the drug to be reduced compared to that administered orally or parenterally while keeping the same local effect. The review article is made with an objective to compile information about various existing modern technologies developed to provide greater patient compliance and reduce the undesirable side effect of the drugs. In conclusion, aerosol antibiotic delivery appears as one of the best technologies for the treatment of pulmonary infectious diseases and able to limit the systemic adverse effects related to the high drug dose and to make life easier for the patients.
Published: 2020
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18. A dynamic evolutionary multi-agent system to predict the 3D structure of proteins

Author: Mario Inostroza-Ponta, Luciana Arantes, Pierre Sens, Márcio Dorn, Leonardo de Lima Corrêa, Instituto de Informática da UFRGS (UFRGS), Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), DistributEd aLgorithms and sYStems (DELYS), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-LIP6, Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidad de Santiago de Chile [Santiago] (USACH), and This work was supported by grants from MCT/CNPq [311611/2018-4], FAPERGS, Alexander von HumboldtStiftung (AvH) [BRA 1190826 HFST CAPES-P] - Germany, and was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001. CAPES STICAMSUD - Brazil.
Subjects: Optimization, Quantitative Biology::Biomolecules, 0303 health sciences, Speedup, Theoretical computer science, Multi-agent system, 030302 biochemistry & molecular biology, computer.file_format, Protein structure prediction, Protein Data Bank, Set (abstract data type), 03 medical and health sciences, Structural bioinformatics, Knowledge-based algorithm, Key (cryptography), State space, [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, 030304 developmental biology
Abstract: International audience; The protein structure prediction is one of the key problems in Structural Bioinformatics. The protein function is directly related to its conformation and the folding can provide to researchers better understandings about the protein roles in the cell. Several computational methods have been proposed over the last decades to tackle the problem. In this paper, we propose an ab initio algorithm with database information for the protein structure prediction problem. We do so by designing some versions of a multi-agent system that use concepts of dynamic distributed evolutionary algorithms to speed up and improve the optimization by better adapting the algorithm to the target protein. The dynamic strategy consists of auto-adapting the number of optimization agents according to the needs and current status of the optimization process. The system is able to scale in/out itself depending on some diversity criteria. The algorithms also take advantage of structural knowledge from the Protein Data Bank to better guide the search and constraint the state space. To validate our computational strategies, we tested them on a set of eight protein sequences. The obtained results were topologically compatible with the experimental correspondent ones, thus corroborating the promising performance of the strategies.
Published: 2020
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19. Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives

Author: Laurent Meijer, Nadège Loaëc, Carole Dubouilh-Benard, Marie-Renée Nourrisson, Yvonnick Loidreau, Thierry Besson, Pascal Marchand, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), ManRos Therapeutics, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Stereochemistry, CK1, CDK5, Pharmaceutical Science, lcsh:Medicine, lcsh:RS1-441, Microwave-assisted chemistry, 01 natural sciences, lcsh:Pharmacy and materia medica, 03 medical and health sciences, chemistry.chemical_compound, Harmine, Protein kinases, Furan, Drug Discovery, Thiophene, [CHIM]Chemical Sciences, 030304 developmental biology, Pyrrole, chemistry.chemical_classification, 0303 health sciences, GSK-3, 010405 organic chemistry, Kinase, Communication, Cyclin-dependent kinase 5, lcsh:R, DYRK1A, 0104 chemical sciences, chemistry, Molecular Medicine, Casein kinase 1, Tricyclic
Abstract: We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1/ε, GSK3 and DYRK1A). As a result, we have identified promising compounds targeting CK1/ε and DYRK1A and displaying micromolar and submicromolar IC50 values.
Published: 2020
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20. Insights into pparγphosphorylation and its inhibition mechanism

Author: Montanari, Roberta, Capelli, Davide, Yamamoto, Keiko, Awaishima, Hirono, Nishikata, Kimina, Barendregt, Arjan, Heck, Albert J R, Loiodice, Fulvio, Altieri, Fabio, Paiardini, Alessandro, Grotessi, Alessandro, Pirone, Luciano, Pedone, Emilia Maria, Peiretti, Franck, Brunel, Jean Michel, Itoh, Toshimasa, Pochetti, Giorgio, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Consiglio Nazionale delle Ricerche [Roma] (CNR), Showa Pharmaceutical University [Tokyo, Japan], Utrecht University [Utrecht], University of Bari Aldo Moro (UNIBA), Sapienza University [Rome], CINECA Consorzio Interuniversitario [Rome, Italy], Institute of biostructures and bioimaging [Naples, Italy] (CNR), Italian Research National Council, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Aix Marseille Université (AMU), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Istituto di Cristallografia (IC), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Institute for Complex Systems [Rome] (CNR - ISC), Department of Biomolecular Mass Spectrometry and Proteomics Group [Utrecht, The Netherlands], Utrecht University [Utrecht]-Utrecht Institute for Pharmaceutical Sciences (UIPS)-Bijvoet Centre for Biomolecular Research [Utrecht, The Netherlands], Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institute of biostructures and bioimaging (IBB), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Instruct Integrating Biology 1579/ Associazione Italiana per la Ricerca sul Cancro (AIRC) MFAG 20447, Consiglio Nazionale delle Ricerche (CNR), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, and Brunel, Jean Michel
Subjects: PPARgamma, Phosphorylation sites, protein binding, phenylpropionates, serine, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, protein conformation, Drug Discovery, amino acidsequence, biphenyl compounds, cyclin-dependent kinase 5, humans, molecular docking simulation, molecular dynamics simulation, mutagenesis, site-directed, mutation, nerve tissue proteins, PPAR gamma, phosphorylation, Amino Acid Sequence, 030304 developmental biology, 0303 health sciences, Chemistry, Cyclin-dependent kinase 5, site-directed, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 3. Good health, Cell biology, Nuclear receptor, Docking (molecular), 030220 oncology & carcinogenesis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Mutagenesis, Site-Directed, Molecular Medicine, Phosphorylation, mutagenesis
Abstract: PPARgamma represents a key target for the treatment of type 2 diabetes and metabolic syndrome. Synthetic antidiabetic drugs activating PPARgamma are accompanied by serious undesirable side effects related to their agonism. In the search for new PPARgamma regulators, inhibitors of PPARgamma phosphorylation on S245 mediated by CDK5 represent an opportunity for the development of an improved generation of antidiabetic drugs acting through this nuclear receptor. We have employed a multidisciplinary approach, including protein-protein docking, X-ray crystallography, NMR, HDX, MD simulations, and site-directed mutagenesis to investigate conformational changes in PPARgamma that impair the ability of CDK5 to interact with PPARgamma and hence inhibit PPARgamma phosphorylation. Finally, we describe an alternative inhibition mechanism adopted by a ligand bound far from the phosphorylation site.
Published: 2020
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21. Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines

Author: Marine Blanchet, Zimei Wu, Weirong Kang, Elliot I.W. Pike, Nicolas Vidal, Jean Michel Brunel, Brent R. Copp, Marie-Lise Bourguet-Kondracki, Melissa M. Cadelis, School of Chemical Sciences [Auckland], University of Auckland [Auckland], Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), YELEN, Laboratoire de chimie et biochimie des substances naturelles, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)
Subjects: Polyamine, Cell Membrane Permeability, Indoles, Gram-negative bacteria, Cell Survival, medicine.drug_class, Antibiotics, Microbial Sensitivity Tests, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, medicine.disease_cause, Hemolysis, 01 natural sciences, Cell Line, Microbiology, 03 medical and health sciences, Gram-Negative Bacteria, Drug Discovery, medicine, Humans, [CHIM]Chemical Sciences, indolglyoxylamide, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, Cryptococcus neoformans, Doxycycline, 0303 health sciences, potentiation, biology, 010405 organic chemistry, Chemistry, Pseudomonas aeruginosa, Hydrolysis, Organic Chemistry, General Medicine, biology.organism_classification, Antimicrobial, Anti-Bacterial Agents, Cephalosporins, 3. Good health, 0104 chemical sciences, Acinetobacter baumannii, indole, antimicrobial, Spermine, Bacteria, Signal Transduction, medicine.drug
Abstract: International audience; A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, intrinsic activity was typically observed towards Gram-positive bacteria and the fungus Cryptococcus neoformans, with notable exceptions being the 5-bromo-and 6-chloro-indole analogues which also exhibited modest activity (MIC 34-50 µM) towards the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. Several analogues enhanced the activity of doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, E. coli, K. pneumoniae and Acinetobacter baumannii. Of particular note was the identification of five antibiotic enhancing analogues (5-Br, 7-F, 5-Me, 7-Me, 7-OMe) which also exhibited low to no cytotoxicity and red blood cell haemolytic properties. The mechanisms of action of the 5-Br and 7-F analogues were attributed to the ability to disrupt the integrity of, and depolarize, bacterial membranes.
Published: 2019
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22. Enterobacter spp.: update on taxonomy, clinical aspect and emerging antimicrobial resistance

Author: Anne Davin-Regli, Jean-Marie Pagès, Jean-Philippe Lavigne, Membranes et cibles thérapeutiques (MCT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA)-Aix Marseille Université (AMU), Virulence bactérienne et maladies infectieuses (VBMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), and rosa, emmanuelle
Subjects: Microbiology (medical), 0303 health sciences, General Immunology and Microbiology, 030306 microbiology, Epidemiology, [SDV]Life Sciences [q-bio], Public Health, Environmental and Occupational Health, Virulence, Enterobacter, Review, Biology, biology.organism_classification, Enterobacter aerogenes, Phenotype, Microbiology, Multiple drug resistance, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Infectious Diseases, Antibiotic resistance, [CHIM] Chemical Sciences, [CHIM]Chemical Sciences, Efflux, Bacteria, 030304 developmental biology
Abstract: International audience; The genus Enterobacter is a member of the ESKAPE group, which contains the major resistant bacterial pathogens. First described in 1960, this group member has proven to be more complex as a result of the exponential evolution of phenotypic and genotypic methods. Today, 22 species belong to the Enterobacter genus. These species are described in the environment and have been reported as opportunistic pathogens in plants, animals, and humans. The pathogenicity/virulence of this bacterium remains rather unclear due to the limited amount of work performed to date in this field. In contrast, its resistance against antibacterial agents has been extensively studied. In the face of antibiotic treatment, it is able to manage different mechanisms of resistance via various local and global regulator genes and the modulation of the expression of different proteins, including enzymes (β-lactamases, etc.) or membrane transporters, such as porins and efflux pumps. During various hospital outbreaks, the Enterobacter aerogenes and E. cloacae complex exhibited a multidrug-resistant phenotype, which has stimulated questions about the role of cascade regulation in the emergence of these well-adapted clones.
Published: 2019
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23. Nutrient depletion may trigger the Yersinia pestis OmpR‐EnvZ regulatory system to promote flea‐borne plague transmission

Author: Lionel Koch, Amélie Dewitte, Sébastien Bontemps-Gallo, Florent Sebbane, Etienne Raphaël, Pradel Elizabeth, Frank C. Gherardini, Fabrice Biot, Marion Fernandez, Angéline Reboul, Université de Lille, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Interactions cellulaires et moléculaires des bactéries pathogènes avec l'hôte, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut de Recherche Biomédicale des Armées (IRBA), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA)
Subjects: Flea, Yersinia pestis, animal diseases, [SDV]Life Sciences [q-bio], Porins, Microbiology, Article, 03 medical and health sciences, Nutrient, Bacterial Proteins, Expression pattern, Animals, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Plague, 0303 health sciences, biology, Osmotic concentration, 030306 microbiology, Stomach, fungi, Biofilm, Nutrients, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, biology.organism_classification, Enzyme Activation, Biofilms, Porin, Trans-Activators, Siphonaptera, bacteria, Bacteria, Bacterial Outer Membrane Proteins
Abstract: The flea's lumen gut is a poorly documented environment where the agent of flea-borne plague, Yersinia pestis, must replicate to produce a transmissible infection. Here, we report that both the acidic pH and osmolarity of the lumen's contents display simple harmonic oscillations with different periods. Since an acidic pH and osmolarity are two of three known stimuli of the OmpR-EnvZ two-component system in bacteria, we investigated the role and function of this Y. pestis system in fleas. By monitoring the in vivo expression pattern of three OmpR-EnvZ-regulated genes, we concluded that the flea gut environment triggers OmpR-EnvZ. This activation was not, however, correlated with changes in pH and osmolarity but matched the pattern of nutrient depletion (the third known stimulus for OmpR-EnvZ). Lastly, we found that the OmpR-EnvZ and the OmpF porin are needed to produce the biofilm that ultimately obstructs the flea's gut and thus hastens the flea-borne transmission of plague. Taken as a whole, our data suggest that the flea gut is a complex, fluctuating environment in which Y. pestis senses nutrient depletion via OmpR-EnvZ. Once activated, the latter triggers a molecular program (including at least OmpF) that produces the biofilm required for efficient plague transmission.
Published: 2019
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24. New insights into the tetrameric family of the Fur metalloregulators

Author: Isabelle Michaud-Soret, Serge Crouzy, L. Arnaud, Philippe Carpentier, Serge Nader, Julien Pérard, Groupe modélisation et chimie théorique (MCT), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Biocatalyse (BIOCAT ), Biologie des Métaux (BioMet), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: inorganic chemicals, Subfamily, Mutant, Regulator, General Biochemistry, Genetics and Molecular Biology, Biomaterials, 03 medical and health sciences, chemistry.chemical_compound, Tetramer, Bacterial Proteins, Transcription (biology), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular interactions, Animals, Quaternary structure, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Potential of mean force, Gene, 030304 developmental biology, 0303 health sciences, integumentary system, Chemistry, 030302 biochemistry & molecular biology, Metals and Alloys, Ferric uptake, Metal homeostasis, Iron uptake, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Repressor Proteins, Biochemistry, Mutation, bacteria, Structure of metalloregulators, Protein quaternary structure, General Agricultural and Biological Sciences, DNA, Spiruroidea
Abstract: International audience; The ferric uptake regulator (Fur) belongs to the family of the metal-responsive transcriptional regulators. Fur is a global regulator found in all proteobacteria. It controls the transcription of a wide variety of genes involved in iron metabolism but also in oxidative stress or virulence factor synthesis. As a general view, Fur proteins were considered to be dimeric proteins both in solution and when bound to DNA. However, our recent data demonstrate that Fur proteins can be classified into two subfamilies, according to their quaternary structure. The group of dimers is represented by E. coli, V. cholerae and Y. pestis Fur and the group of highly stable tetramers by P. aeruginosa and F. tularensis Fur. Here, another tetrameric structure of a PaFur mutant containing manganese and zinc metal ions is described. Through biochemical, structural and computational studies, we have deciphered the important structural characteristics of the tetramers and studied the main interactions responsible for their strength. Potential or mean force calculations for tetramer formation have been determinant to quantify these interactions. Moreover calculations allow us to propose that some conserved residues prevent the tetramerization in the subfamily of dimeric Fur.
Published: 2019
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25. 6-Bromoindolglyoxylamido derivatives as antimicrobial agents and antibiotic enhancers

Author: Brent R. Copp, Marie-Lise Bourguet-Kondracki, Steven A. Li, Kenneth Sue, Melissa M. Cadelis, Marine Blanchet, Jean Michel Brunel, Nicolas Vidal, School of Chemical Sciences [Auckland], University of Auckland [Auckland], Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), YELEN, Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Auckland Medical Research Foundation (1116001), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: Erythrocytes, Indoles, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Antibiotics, Pharmaceutical Science, Spermine, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, Anti-Infective Agents, polyamine, Drug Discovery, Polyamines, 0303 health sciences, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Antimicrobial, Anti-Bacterial Agents, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Medicine, Antibacterial activity, bromoindole, Cell Survival, medicine.drug_class, Microbial Sensitivity Tests, Gram-Positive Bacteria, Hemolysis, Cell Line, Microbiology, 03 medical and health sciences, Drug Resistance, Bacterial, Gram-Negative Bacteria, medicine, Humans, [CHIM]Chemical Sciences, Molecular Biology, Escherichia coli, 030304 developmental biology, potentiation, 030306 microbiology, Pseudomonas aeruginosa, Organic Chemistry, Fungi, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, chemistry, antimicrobial, Polyamine, Bacteria
Abstract: International audience; Dedication In memory of Dr. Jiayi (Jane) Wang. Abstract The combination of increased incidence of drug-resistant strains of bacteria and a lack of novel drugs in development creates an urgency for the search for new antimicrobials. Initial screening of compounds from an in-house library identified two 6-bromoindolglyoxylamide polyamine derivatives that exhibited intrinsic antimicrobial activity towards Gram-positive bacteria, Staphylococcus aureus and S. intermedius with one of the compounds also displaying in vitro antibiotic enhancing properties against the resistant Gram-negative bacterium Pseudomonas aeruginosa. A series of 6-bromo derivatives were prepared and biologically evaluated, identifying analogues with enhanced antibacterial activity towards Escherichia coli and with moderate to excellent antifungal properties. The mechanism of action of one of the compounds was attributed to rapid membrane permeabilisation and depolarisation in both Gram-positive and Gram-negative bacteria.
Published: 2019

26. Antibiotic Adjuvants: Make Antibiotics Great Again!

Author: Jean Michel Brunel, Hana Douafer, Véronique Andrieu, Otto Phanstiel, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), University of Central Florida [Orlando] (UCF), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), and COMBE, Isabelle
Subjects: medicine.drug_class, Antibiotic resistance, medicine.medical_treatment, Antibiotics, Drug resistance, 01 natural sciences, beta-Lactamases, Bacterial genetics, Microbiology, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Bacterial Proteins, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cell Wall, Drug Resistance, Multiple, Bacterial, Drug Discovery, medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Beta-Lactamase Inhibitors, 030304 developmental biology, Adjuvants, Pharmaceutic, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Membranes, biology, Bacteria, Chemistry, Inhibitors, biology.organism_classification, Antimicrobial agents, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 0104 chemical sciences, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Anti-Bacterial Agents, 010404 medicinal & biomolecular chemistry, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Molecular Medicine, ATP-Binding Cassette Transporters, Efflux, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, beta-Lactamase Inhibitors, Adjuvant, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract: Multiple approaches have been developed to combat bacterial resistance. However, the combination of antibiotic resistance mechanisms by bacteria and the limited number of effective antibiotics available decreases the effective interventions for the treatment of current bacterial infections. This review covers the many ways that bacteria resist antibiotics including antibiotic target modification, the use of efflux pumps, and antibiotic inactivation. As a pertinent example, the use of beta lactamase inhibitors in combination with β-lactam containing antibiotics is discussed in detail. The solution to emerging antibiotic resistance may involve combination therapies of existing antibiotics and potentiating adjuvants, which re-empower the antibiotic agent to become efficacious against the resistant strain of interest. We report herein that a reasoned adjuvant design permits one to perform polypharmacy on bacteria by not only providing greater internal access to the codosed antibiotics but also by de-energizing the efflux pumps used by the bacteria to escape antibiotic action.
Published: 2019
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27. Three-Component Synthesis of Chromeno β-Lactam Hybrids for Inflammation and Cancer Screening

Author: Jean Michel Brunel, Younes Ghasemi, Gyula Batta, Saghi Sepehri, Carole Digiorgio, Amin Reza Akbarizadeh, Maryam Sasanipour, Milad Mohkam, Nassim Borazjani, Mohammad Ghanbari, Edward Turos, Javad Ameri Rad, Aliasghar Jarrahpour, Maryam Behzadi, brunel, jean michel, Shiraz University (Shiraz University ), Ardabil University of Medical Sciences, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Islamic Azad University, University of Debrecen Egyetem [Debrecen], University of South Florida [Tampa] (USF), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and University of South Florida (USF)
Subjects: [SDV]Life Sciences [q-bio], Drug Evaluation, Preclinical, DABCO, 01 natural sciences, β-Lactams, Mice, chemistry.chemical_compound, one-pot three- component synthesis, Neoplasms, Drug Discovery, [CHIM] Chemical Sciences, Tumor Cells, Cultured, Cytotoxicity, Malononitrile, anti-inflammatory, 0303 health sciences, Molecular Structure, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Anti-Inflammatory Agents, Non-Steroidal, Hep G2 Cells, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], colon cancer, Lactam, cytotoxicity, Two-dimensional nuclear magnetic resonance spectroscopy, Heteronuclear single quantum coherence spectroscopy, Cell Survival, Stereochemistry, dihydropyrano[c]-chromene, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, beta-Lactams, anticancer, Adduct, Structure-Activity Relationship, 03 medical and health sciences, Animals, Humans, [CHIM]Chemical Sciences, Benzopyrans, Cell Proliferation, 030304 developmental biology, Octane, Inflammation, Pharmacology, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, [CHIM.ORGA] Chemical Sciences/Organic chemistry, 0104 chemical sciences, RAW 264.7 Cells, chemistry, tetrahydro-4H-chromene, Drug Screening Assays, Antitumor, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Highly diastereoselective synthesis of chromeno β-lactam hybrids was achieved by an efficient one-pot three-component reaction. With this procedure, the desired β-lactam products were obtained in good yields and with exclusive cis stereoselection, by combining a variety of benzaldehydes, malononitrile, and either 5,5-dimethylcyclohexane-1,3-dione or 4-hydroxycoumarin in the presence of 1,4-diazabicyclo [2.2.2]octane under reflux conditions. These adducts were structurally characterized on the basis of IR, 1D and 2D NMR spectra, X-ray analysis, H-H COSY and H-C HSQC two-dimensional NMR experiments, and elemental analysis. Each of the synthesized compounds was screened for anti-inflammatory and anticancer activities. β-Lactams 5b and 8b showed a 53.4 and 19.8 anti-inflammatory ratio, respectively, and 5b appeared more active than the well-known dexamethasone corticosteroid used for the treatment of rheumatoid and skin inflammation. β-Lactams 5a, 5b, 5e, 5f, 5g, 8c, 8j and 8p also showed good antitumor activity against the SW1116 (colon cancer) cell line without notable cytotoxicity towards the HepG2 control cell line.
Published: 2019
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28. Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria

Author: Julia Vergalli, Bert van den Berg, James H. Naismith, Lucile Moynié, Anne Davin-Regli, Igor Bodrenko, Muriel Masi, Mathias Winterhalter, Silvia Acosta-Gutierrez, Matteo Ceccarelli, Jean-Marie Pagès, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Département Microbiologie (Dpt Microbio), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA)
Subjects: Gram-negative bacteria, porins, [SDV]Life Sciences [q-bio], Microbiology, antibiotics, 03 medical and health sciences, Enterobacteriaceae, Drug Resistance, Bacterial, Inner membrane, 0303 health sciences, General Immunology and Microbiology, biology, 030306 microbiology, Cell Membrane, Biological membrane, Biological Transport, biology.organism_classification, Small molecule, General bacterial porin family, Anti-Bacterial Agents, diffusive transport, Infectious Diseases, Biophysics, Efflux, Bacterial outer membrane, Intracellular, Bacterial Outer Membrane Proteins
Abstract: International audience; Gram-negative bacteria and their complex cell envelope, which comprises an outer membrane and an inner membrane, are an important and attractive system for studying the translocation of small molecules across biological membranes. In the outer membrane of Enterobacteriaceae, trimeric porins control the cellular uptake of small molecules, including nutrients and antibacterial agents. The relatively slow porin-mediated passive uptake across the outer membrane and active efflux via efflux pumps in the inner membrane creates a permeability barrier. The synergistic action of outer membrane permeability, efflux pump activities and enzymatic degradation efficiently reduces the intracellular concentrations of small molecules and contributes to the emergence of antibiotic resistance. In this Review, we discuss recent advances in our understanding of the molecular and functional roles of general porins in small-molecule translocation in Enterobacteriaceae and consider the crucial contribution of porins in antibiotic resistance.
Published: 2019
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29. Outer Membrane Porins

Author: Muriel Masi, Jean-Marie Pagès, Mathias Winterhalter, Membranes et cibles thérapeutiques (MCT), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: 0303 health sciences, biology, 030306 microbiology, Chemistry, Membrane transport protein, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Small molecule, 03 medical and health sciences, Membrane, Structural biology, Porin, Biophysics, biology.protein, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Bacterial outer membrane, Energy source, Biogenesis, 030304 developmental biology
Abstract: The transport of small molecules across membranes is essential for the import of nutrients and other energy sources into the cell and, for the export of waste and other potentially harmful byproducts out of the cell. While hydrophobic molecules are permeable to membranes, ions and other small polar molecules require transport via specialized membrane transport proteins . The two major classes of membrane transport proteins are transporters and channels. With our focus here on porins-major class of non-specific diffusion channel proteins , we will highlight some recent structural biology reports and functional assays that have substantially contributed to our understanding of the mechanism that mediates uptake of small molecules, including antibiotics, across the outer membrane of Enterobacteriaceae . We will also review advances in the regulation of porin expression and porin biogenesis and discuss these pathways as new therapeutic targets.
Published: 2019
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30. molecules 5-Arylideneimidazolones with Amine at Position 3 as Potential Antibiotic Adjuvants against Multidrug Resistant Bacteria

Author: Wojciech Nitek, Jean-Marie Pagès, Karolina Witek, Ewa Żesławska, Elżbieta Karczewska, Sandrine Alibert, Joanna Czekajewska, Aneta Kaczor, Katarzyna Kieć-Kononowicz, Annamaria Lubelska, Gniewomir Latacz, Jadwiga Handzlik, Sabina Podlewska, Faculty of Chemistry - Jagiellonian University, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Department of Technology and Biotechnology of Drugs, Jagiellonian University - Medical College, Department of Pharmaceutical Microbiology, Jagiellonian, Faculty of Chemistry, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Department of Pharmaceutical Microbiology, jagiellonian university, Aix-Marseille Univ. and Service de Santé des Armées, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), and rosa, emmanuelle
Subjects: Models, Molecular, Penicillin binding proteins, microdilution assays, [SDV]Life Sciences [q-bio], Antibiotics, RTE studies, Staphylococcus aureus, Pharmaceutical Science, MRSA, 01 natural sciences, Analytical Chemistry, Drug Resistance, Multiple, Bacterial, [CHIM] Chemical Sciences, Drug Discovery, Amines, 0303 health sciences, allosteric modulation, Molecular Structure, biology, Chemistry, Imidazoles, Enterobacter aerogenes, Anti-Bacterial Agents, 3. Good health, [SDV] Life Sciences [q-bio], Chemistry (miscellaneous), multi-drug resistance, Molecular Medicine, Efflux, Stereochemistry, medicine.drug_class, Microbial Sensitivity Tests, 010402 general chemistry, Dimroth rearrangement, ADMET in vitro, Article, lcsh:QD241-441, Structure-Activity Relationship, 03 medical and health sciences, Bacterial Proteins, lcsh:Organic chemistry, 5-arylideneimidazolones, medicine, Humans, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, 030304 developmental biology, Bacteria, Efflux pump, Organic Chemistry, Hydrogen Bonding, biology.organism_classification, 0104 chemical sciences, Multiple drug resistance, Docking (molecular)
Abstract: Searching for new chemosensitizers of bacterial multidrug resistance (MDR), chemical modifications of (Z)-5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one (6) were performed. New compounds (7&ndash, 17), with fused aromatic rings at position 5, were designed and synthesized. Crystallographic X-ray analysis proved that the final compounds (7&ndash, 17) were substituted with tertiary amine-propyl moiety at position 3 and primary amine group at 2 due to intramolecular Dimroth rearrangement. New compounds were evaluated on their antibiotic adjuvant properties in either Gram-positive or Gram-negative bacteria. Efflux pump inhibitor (EPI) properties towards the AcrAB-TolC pump in Enterobacter aerogenes (EA289) were investigated in the real-time efflux (RTE) assay. Docking and molecular dynamics were applied to estimate an interaction of compounds 6&ndash, 17 with penicillin binding protein (PBP2a). In vitro ADME-Tox properties were evaluated for compound 9. Most of the tested compounds reduced significantly (4-32-fold) oxacillin MIC in highly resistant MRSA HEMSA 5 strain. The anthracene-morpholine derivative (16) was the most potent (32-fold reduction). The tested compounds displayed significant EPI properties during RTE assay (37&ndash, 97%). The naphthyl-methylpiperazine derivative 9 showed the most potent &ldquo, dual action&rdquo, of both oxacillin adjuvant (MRSA) and EPI (E. aerogenes). Molecular modeling results suggested the allosteric mechanism of action of the imidazolones, which improved binding of oxacillin in the PBP2a active site in MRSA.
Published: 2019
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31. Synthesis and Biological Evaluation of Four New Ricinoleic Acid-Derived 1-O-alkylglycerols

Author: Jean-Marie Pagès, Paul Mosset, Dieudonné Emmanuel Pegnyemb, René Pemha, Victor Kuete, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Université de Dschang, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Université de Yaoundé I, stu-Id28009651, Univesité de Rennes 1, France, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA)
Subjects: Glycerol, Tetracycline, medicine.drug_class, Ricinoleic acid, Antibiotics, Pharmaceutical Science, Gram-Positive Bacteria, 01 natural sciences, Article, 03 medical and health sciences, chemistry.chemical_compound, structure–activity relationship (SAR) studies, Gram-Negative Bacteria, Drug Discovery, medicine, [CHIM]Chemical Sciences, Organic chemistry, antibiotics (gentamicin, tetracycline, ciprofloxacin and ampicillin), lcsh:QH301-705.5, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Alkyl, 030304 developmental biology, alkylglycerol (AKG), ricinoleic acid (RA), antimicrobial activity, chemistry.chemical_classification, 0303 health sciences, 010405 organic chemistry, Antimicrobial, Anti-Bacterial Agents, 0104 chemical sciences, 3. Good health, Ciprofloxacin, lcsh:Biology (General), chemistry, Azide, Ricinoleic Acids, Lead compound, medicine.drug
Abstract: A series of novel substituted 1-O-alkylglycerols (AKGs) containing methoxy (8), gem-difluoro (9), azide (10) and hydroxy (11) group at 12 position in the alkyl chain were synthesized from commercially available ricinoleic acid (12). The structures of these new synthesized AKGs were established by NMR experiments as well as from the HRMS and elementary analysis data. The antimicrobial activities of the studied AKGs 8−11 were evaluated, respectively, and all compounds exhibited antimicrobial activity to different extents alone and also when combined with some commonly used antibiotics (gentamicin, tetracycline, ciprofloxacin and ampicillin). AKG 11 was viewed as a lead compound for this series as it exhibited significantly higher antimicrobial activity than compounds 8−10.
Published: 2020
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32. Corrigendum: A unique peptide deformylase platform to rationally design and challenge novel active compounds

Author: Thierry Meinnel, Karim Hamiche, Rodolphe Alves de Sousa, Carmela Giglione, Laure Maigre, Alexis Denis, Sonia Fieulaine, Jean-Michel Bolla, Isabelle Artaud, Mickael Alimi, Abbass Taleb, Jean-Marie Pagès, Interactions et mécanismes d’assemblage des protéines et des peptides (IMAPP), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Membranes et cibles thérapeutiques (MCT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA)-Aix Marseille Université (AMU), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), GlaxoSmithKline, Glaxo Smith Kline, Maturation des proteines, destinée cellulaire et thérapeutique (PROMTI), Département Biologie des Génomes (DBG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), SERRE, Marie-Claude, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: 0303 health sciences, Multidisciplinary, Computer science, Published Erratum, [SDV]Life Sciences [q-bio], Computational biology, Corrigenda, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Peptide deformylase, 0302 clinical medicine, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.
Published: 2017
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33. Microspectrometric insights on the uptake of antibiotics at the single bacterial cell level

Author: Bertrand Cinquin, Jean-Marie Pagès, Robert A. Stavenger, Elizabeth Pinet, Scott D. Mills, Laure Maigre, Matthieu Réfrégiers, Jacqueline Chevalier, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Membranes et cibles thérapeutiques (MCT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA)-Aix Marseille Université (AMU), Transporteurs membranaires, chimioresistance et drug-design (TMCD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), GlaxoSmithKline, Glaxo Smith Kline, AstraZeneca, rosa, emmanuelle, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, Cell, Drug design, Drug resistance, Biology, Article, Bacterial cell structure, Microbiology, 03 medical and health sciences, Single-cell analysis, DISCO beamline (synchrotron Soleil), Drug Resistance, Bacterial, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Bacteria, Molecular Structure, 030306 microbiology, Bacterial multidrug resistance, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gram-negative, Anti-Bacterial Agents, 3. Good health, Multiple drug resistance, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Microspectrophotometry, Biophysics, Single-Cell Analysis, Reactive Oxygen Species, Oxidation-Reduction
Abstract: International audience; Bacterial multidrug resistance is a significant health issue. A key challenge, particularly in Gram-negative antibacterial research, is to better understand membrane permeation of antibiotics in clinically relevant bacterial pathogens. Passing through the membrane barrier to reach the required concentration inside the bacterium is a pivotal step for most antibacterials. Spectrometric methodology has been developed to detect drugs inside bacteria and recent studies have focused on bacterial cell imaging. Ultimately, we seek to use this method to identify pharmacophoric groups which improve penetration, and therefore accumulation, of small-molecule antibiotics inside bacteria. We developed a method to quantify the time scale of antibiotic accumulation in living bacterial cells. Tunable ultraviolet excitation provided by DISCO beamline (synchrotron Soleil) combined with microscopy allows spectroscopic analysis of the antibiotic signal in individual bacterial cells. Robust controls and measurement of the crosstalk between fluorescence channels can provide real time quantification of drug. This technique represents a new method to assay drug translocation inside the cell and therefore incorporate rational drug design to impact antibiotic uptake. Multi-drug resistant (MDR) Gram-negative bacteria such as Escherichia coli (E. coli) and other Enterobacteriaceae are spreading rapidly and in many cases are capable of producing severe infections that can eventually lead to death (135 000 infections in Europe and 215 000 in the USA annually) and contributing to the concept of the ESKAPE alert in clinical bacteriology and emerging pathogens 1,2. The widespread use, and misuse, of antibiotics results in the generation/release of antibiotic concentration gradients in the environment, including humans, animals, water, etc 3,4. Consequently, bacteria are frequently exposed to subinhibitory concentrations of antibiotics leading to the evolution, selection and potential spreading of antibiotic resistance 3,5,6. Different resistance mechanisms have been highlighted and include: (i) drug inactivation or modification by enzymatic action (e.g. ß-lactamase, acetylase). (ii) Alteration/mutation or masking of targets (e.g. penicillin binding proteins, Type II topoisomerases). (iii) Alteration of metabolic pathways: bacteria resist antimicrobial agents by using alternate pathways than those inhibited by the molecule, or bacteria increase the production of the target metabolite (e.g. using pre-synthesized folic acid, increasing the rate of folic acid synthesis). (iv) Changing the membrane permeability (e.g. downregulation of porins, overexpression of efflux pumps). Employing this last strategy, the bacterium is able to manage the intra-cellular concentration of antibiotics by modulating the entry or the ejection of active agents 7. Thereby, the effective concentration of drug is never reached inside the cell and consequently its activity is minimized. Furthermore, the relatively low concentration of antibiotic inside the bacterium can promote adaptation by developing the expression/selection of other resistance mechanisms 8,9. Thus, the " multi " in the term MDR can be read at different levels: multi because of the multiple antibiotic classes a bacterium can be resistant to, but also because multiple and various mechanisms contribute to the bacterial survival in the presence of antibacterial agents 10. Deciphering the biochemical basis and the mechanistic processes underlying the accumulation of antibacterial agents is essential to design and develop antibiotics that can achieve higher, more effective intracellular concentrations and avoid further spreading of resistance. This is particularly important with the continuing emergence and the worldwide distribution of MDR bacteria and the paucity of new antibacterial agents to treat MDR bacteria 11–13. The paper of 1 DISCO beamline
Published: 2016
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34. Synthesis of N,N′-bis(5-arylidene-4-oxo-3,5-dihydro-4H-imidazol-2-yl)diamines bearing various linkers and biological evaluation as potential inhibitors of kinases

Author: Wacothon Karime Coulibaly, Ludovic Paquin, Anoubilé Benié, Yves-Alain Bekro, Jean Pierre Bazureau, Emilie Durieu, Laurent Meijer, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie Bioorganique et des Substances Naturelles (LCBOSN), Université Abobo-Adjamé, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Agence Universitaire de la Francophonie AUF [0486], French National Cancer Institute [PRIR 04-8390, ACI 04-2254], 'Fonds Unique Interministeriel' (FUI) PHARMASEA project, Association France-Alzheimer (Finistere), CRITT-Sante Bretagne, Fondation Jerome Lejeune, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)
Subjects: Swine, PROTEIN-KINASES, 5-Arylidene-imidazolinone, Ethylenediamine, SALTS, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, law.invention, Glycogen Synthase Kinase 3, Mice, chemistry.chemical_compound, law, 5-dihydro-4H-imidazol-2-yl)diamine, Drug Discovery, Diamino linker, Microwaves, Biological evaluation, Reaction conditions, 0303 health sciences, Solvent free, Molecular Structure, Kinase, General Medicine, Protein-Tyrosine Kinases, ANTIMALARIAL-DRUG DEVELOPMENT, Microwave irradiation, Sulphur/nitrogen displacement, Stereochemistry, Diamines, Protein Serine-Threonine Kinases, Structure-Activity Relationship, 03 medical and health sciences, LEUCETTAMINE B, Animals, Protein Kinase Inhibitors, Walden inversion, 030304 developmental biology, Pharmacology, Solvent-free, Glycogen Synthase Kinase 3 beta, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, Rats, 0104 chemical sciences, Piperazine, chemistry, Kinase inhibitors, N '-bis(5-arylidene-4-oxo-3
Abstract: The synthesis in 4 steps of new N , N ′-bis(5-arylidene-4-oxo-3,5-dihydro-4 H -imidazol-2-yl)diamines issued from various symmetric primary diamines as linkers was reported. The key step of our strategy has been the sulphur/nitrogen displacement of ( 5Z )-5-arylidene-2-ethylsulfanyl-3,5-dihydro-4 H -imidazol-4-ones 6 with respectively ethylenediamine 7a , piperazine 7b and N , N ′-bis(3-aminopropyl)piperazine 7c using solvent-free reaction conditions under microwave irradiation with retention of configuration. These compounds were tested for their kinase inhibitory potencies toward four kinases (GSK-3α/β, DYRK1A, CLK1 and CLK3).
Published: 2012
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35. Selectivity, Cocrystal Structures, and Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors Derived from the Marine Sponge Alkaloid Leucettamine B

Author: Claude Cochet, Guillaume Burgy, François Carreaux, Meera Soundararajan, Panagis Filippakopoulos, Anselm Erich Oberholzer, Emilie Durieu, Laurent Meijer, Jean Pierre Bazureau, Ralf S. Schmid, Florent Delhommel, Jonathan M. Elkins, Donald C. Lo, Tania Tahtouh, Laurence H. Pearl, Stefan Knapp, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Nuffield Department of Clinical Medicine [Oxford], University of Oxford, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford], Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Models, Molecular, DYRK1B, DYRK1A, Crystallography, X-Ray, 01 natural sciences, Chromatography, Affinity, Rats, Sprague-Dawley, CLK1, Amyloid beta-Protein Precursor, Mice, chemistry.chemical_compound, Drug Discovery, 0303 health sciences, Cell Death, Molecular Structure, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Kinase, Chemistry, Pyramidal Cells, Imidazoles, Brain, Stereoisomerism, Protein-Tyrosine Kinases, Recombinant Proteins, Porifera, Neuroprotective Agents, Biochemistry, Molecular Medicine, Protein Binding, Glutamic Acid, Dioxoles, In Vitro Techniques, Protein Serine-Threonine Kinases, Cell Line, Structure-Activity Relationship, 03 medical and health sciences, Alkaloids, Animals, Humans, Protein kinase A, Protein Kinase Inhibitors, 030304 developmental biology, Protein-Serine-Threonine Kinases, 010405 organic chemistry, Cyclin-Dependent Kinase 2, Cyclin-dependent kinase 2, Tyrosine phosphorylation, Rats, 0104 chemical sciences, biology.protein
Abstract: International audience; DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease.
Published: 2012
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36. Nitric oxide inhibits the ATPase activity of the chaperone-like AAA+ ATPase CDC48, a target for S-nitrosylation in cryptogein signalling in tobacco cells

Author: Stéphane Bourque, David Wendehenne, Jean Borges Bertoldo, Hernán Terenzi, Jeremy Astier, Angélique Besson-Bard, Olivier Lamotte, Agroécologie [Dijon], Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Universidade Federal de Santa Catarina = Federal University of Santa Catarina [Florianópolis] (UFSC), Agence Nationale de la Recherche [BLAN07-2_184783 PIANO], Burgundy State [PARI AGRALE 8], FAPESC (Fundacao de Apoio a Pesquisa Cientifica e Tecnologica do Estado de Santa Catarina), CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico), MCT/FINEP (Ministerio da Ciencia e Tecnologia/Financiadora de Estudos e Projetos), CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior), Ministere Francais de l'Education Nationale, de la Recherche et de la Technologie, and Burgundy Sate [FABER project] [PARI AGRALE 8]
Subjects: Models, Molecular, 0106 biological sciences, Protein Conformation, [SDV]Life Sciences [q-bio], Nicotiana tabacum, ATPase, Molecular Sequence Data, Cell Cycle Proteins, Nitric Oxide, 01 natural sciences, Biochemistry, cryptogein, Fungal Proteins, 03 medical and health sciences, Valosin Containing Protein, Tobacco, Amino Acid Sequence, nitric oxide (no), Molecular Biology, Plant Proteins, 030304 developmental biology, Adenosine Triphosphatases, 0303 health sciences, biology, Walker motifs, Cell Biology, S-Nitrosylation, cell division cycle 48 (cdc48), Biotic stress, biology.organism_classification, AAA proteins, Protein Structure, Tertiary, Elicitor, Chaperone (protein), [SDE]Environmental Sciences, biology.protein, s-nitrosylation, plant defence responses, 010606 plant biology & botany
Abstract: NO has important physiological functions in plants, including the adaptative response to pathogen attack. We previously demonstrated that cryptogein, an elicitor of defence reaction produced by the oomycete Phytophthora cryptogea , triggers NO synthesis in tobacco. To decipher the role of NO in tobacco cells elicited by cryptogein, in the present study we performed a proteomic approach in order to identify proteins undergoing S-nitrosylation. We provided evidence that cryptogein induced the S-nitrosylation of several proteins and identified 11 candidates, including CDC48 (cell division cycle 48), a member of the AAA+ ATPase (ATPase associated with various cellular activities) family. In vitro , NtCDC48 ( Nicotiana tabacum CDC48) was shown to be poly-S-nitrosylated by NO donors and we could identify Cys 110 , Cys 526 and Cys 664 as a targets for S-nitrosylation. Cys 526 is located in the Walker A motif of the D2 domain, that is involved in ATP binding and was previously reported to be regulated by oxidative modification in Drosophila . We investigated the consequence of NtCDC48 S-nitrosylation and found that NO abolished NtCDC48 ATPase activity and induced slight conformation changes in the vicinity of Cys 526 . Similarly, substitution of Cys 526 by an alanine residue had an impact on NtCDC48 activity. More generally, the present study identified CDC48 as a new candidate for S-nitrosylation in plants facing biotic stress and further supports the importance of Cys 526 in the regulation of CDC48 by oxidative/nitrosative agents.
Published: 2012
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37. Antimalarial drug discovery: targeting protein kinases

Author: Laurent Meijer, Christian Doerig, Controle de la Proliferation Cellulaire Chez Plasmodium Falciparum, Institut National de la Santé et de la Recherche Médicale (INSERM), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Plasmodium falciparum, MESH: Malaria, Clinical Biochemistry, Computational biology, MESH: Drug Design, Biology, Plasmodium, Antimalarials, 03 medical and health sciences, parasitic diseases, Drug Discovery, polycyclic compounds, medicine, Animals, Humans, MESH: Protein Kinase Inhibitors, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Kinome, Vector (molecular biology), MESH: Phylogeny, Protein kinase A, Protein Kinase Inhibitors, MESH: Protein Kinases, Phylogeny, MESH: Plasmodium falciparum, 030304 developmental biology, Pharmacology, 0303 health sciences, MESH: Humans, Drug discovery, Kinase, 030302 biochemistry & molecular biology, medicine.disease, biology.organism_classification, MESH: Antimalarials, Virology, Malaria, 3. Good health, Drug Design, Molecular Medicine, Protein Kinases
Abstract: Protein kinases (PKs) are prime targets for drug discovery in a variety of diseases, including cancer and neurodegenerative pathologies. The characterisation of the kinome of the human malaria parasite Plasmodium falciparum has revealed profound divergences, at several levels, between PKs of the parasite and those of its host. Here, the authors review the major issues and recent advances regarding the development of Plasmodium-selective PK inhibitors, with emphasis on target identification and validation, and on structure-based design. The authors also discuss the possibility of interfering with: i) Plasmodium PKs regulating transmission to the mosquito vector; and ii) host PKs that may be required for parasite survival.
Published: 2007
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38. Mitochondrial respiration and genomic analysis provide insight into the influence of the symbiotic bacterium on host trypanosomatid oxygen consumption

Author: Antonio Galina, Luiz Gonzaga, W. De Souza, Allan C. de Azevedo-Martins, Marcelo Einicker-Lamas, Marie-France Sagot, Cecilia C. Klein, Ana Tereza Ribeiro de Vasconcelos, Maria Cristina M. Motta, Ana Carolina Loyola Machado, Luciane Prioli Ciapina, Laboratório de Ultraestrutura Celular Hertha Meyer - IBCCF / UFRJ [Rio de Janeiro], Instituto de Biofísica Carlos Chagas Filho [Rio de Janeiro] (IBCCF / UFRJ), Universidade Federal do Rio de Janeiro (UFRJ)-Universidade Federal do Rio de Janeiro (UFRJ), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Laboratorio Nacional de Computação Cientifica [Rio de Janeiro] (LNCC / MCT), Baobab, Département PEGASE [LBBE] (PEGASE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Laboratório Intermediário de Biomembranas, Universidade Federal do Rio de Janeiro (UFRJ), Laboratório de Bioenergética e Fisiologia Mitocondrial, and European Project: 247073,EC:FP7:ERC,ERC-2009-AdG,SISYPHE(2010)
Subjects: Angomonas deanei, Cellular respiration, 030231 tropical medicine, Respiratory chain, Mitochondrion, Biology, Electron Transport, 03 medical and health sciences, Aposymbiotic, chemistry.chemical_compound, 0302 clinical medicine, Oxygen Consumption, Respiration, Symbiosis, Thenoyltrifluoroacetone, 030304 developmental biology, 0303 health sciences, Oxidase test, Bacteria, fungi, biology.organism_classification, Biological Evolution, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Mitochondria, Infectious Diseases, Biochemistry, chemistry, Gene Expression Regulation, Trypanosomatina, Animal Science and Zoology, Parasitology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: SUMMARYCertain trypanosomatids co-evolve with an endosymbiotic bacterium in a mutualistic relationship that is characterized by intense metabolic exchanges. Symbionts were able to respire for up to 4 h after isolation fromAngomonas deanei. FCCP (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone) similarly increased respiration in wild-type and aposymbiotic protozoa, though a higher maximal O2consumption capacity was observed in the symbiont-containing cells. Rotenone, a complex I inhibitor, did not affectA. deaneirespiration, whereas TTFA (thenoyltrifluoroacetone), a complex II activity inhibitor, completely blocked respiration in both strains. Antimycin A and cyanide, inhibitors of complexes III and IV, respectively, abolished O2consumption, but the aposymbiotic protozoa were more sensitive to both compounds. Oligomycin did not affect cell respiration, whereas carboxyatractyloside (CAT), an inhibitor of the ADP-ATP translocator, slightly reduced O2consumption. In theA. deaneigenome, sequences encoding most proteins of the respiratory chain are present. The symbiont genome lost part of the electron transport system (ETS), but complex I, a cytochrome d oxidase, and FoF1-ATP synthase remain. In conclusion, this work suggests that the symbiont influences the mitochondrial respiration of the host protozoan.
Published: 2015
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39. Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors

Author: Gérald Guillaumet, Olivier Lozach, Pascal Bonnet, Said Lazar, Rajâa Boulahjar, Laurent Meijer, Aziz Ouach, Yves Troin, Mohamed Akssira, Christiane Guguen-Guillouzo, Rémy Le Guével, Sylvain Routier, Stéphane Bourg, Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme ImPACcell (ImPACcell), Laboratoire de Chimie, Bioorganique et analytique, Université Hassan II [Casablanca] (UH2MC), Institut de Chimie de Clermont-Ferrand (ICCF), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The authors thank the CNRS valorization service (A.O. retribution), Cancéropôle Grand Ouest axis 'Valorisation des produits de la mer', Association pour la Recherche contre le Cancer, the Program Hubert Curien 'Volubilis', and the 'Ligue Nationale contre le Cancer (Comité Grand-Ouest)' for financial support., Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molécules et cibles thérapeutiques (MCT), ManRos Therapeutics, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Interactions Cellulaires et Moléculaires, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR98-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie Physique & de Chimie Bioorganique, URAC 22 (LCPCB), Faculte des sciences et Techniques Mohammedia [Casablanca] (FSTM), Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), Laboratoire de Chimie des Hétérocycles et des Glucides (LCHG), Ecole Nationale Supérieure de Chimie de Clermont-Ferrand (ENSCCF), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-SIGMA Clermont (SIGMA Clermont)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS), Bonnefoy, Stéphanie, Génétique fonctionnelle, agronomie et santé (GFAS), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Sigma CLERMONT (Sigma CLERMONT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, animal structures, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, CDK5, Kinase research, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Isoindoles, 01 natural sciences, GSK3, 03 medical and health sciences, Glycogen Synthase Kinase 3, Structure-Activity Relationship, Piperidines, [SDV.CAN] Life Sciences [q-bio]/Cancer, GSK-3, Cell Line, Tumor, Drug Discovery, [CHIM] Chemical Sciences, Humans, [CHIM]Chemical Sciences, IC50, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, Pharmacology, 0303 health sciences, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, Kinase, Cyclin-dependent kinase 5, Organic Chemistry, In vitro toxicology, Cyclin-Dependent Kinase 5, General Medicine, Valmerin, In vitro, 0104 chemical sciences, 3. Good health, Biochemistry, nervous system, Cell culture, Docking (molecular), In vitro assays, Pyridoisoindolone
Abstract: International audience; An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines.
Published: 2015
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40. Disruption of amylase genes by RNA interference affects reproduction in the Pacific oyster Crassostrea gigas

Author: Nathalia Pereira Cavaleiro, Arnaud Huvet, Pierre Boudry, Virgile Quillien, Yoann Thomas, Caroline Fabioux, Marianne Alunno-Bruscia, Jean-Philippe Béguel, Laboratoire des Sciences de l'Environnement Marin (LEMAR) (LEMAR), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Français de Recherche pour l'Exploitation de la Mer - Brest (IFREMER Centre de Bretagne), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Laboratorio Nacional de Computação Cientifica [Rio de Janeiro] (LNCC / MCT), Mer, molécules et santé EA 2160 (MMS), Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), and ANR-08-GENM-0041,Gametogenes,Génomiques de la gamétogénèse chez l'huître creuse Crassostrea gigas(2008)
Subjects: Male, Physiology, in-vivo, Gametogenesis, polymorphism, Amylase, 0303 health sciences, biology, Reproduction, 04 agricultural and veterinary sciences, Pacific oyster, RNA silencing, medicine.anatomical_structure, quality, Amylases, Crassostrea, Dynamic energy budget, Female, RNA Interference, Alpha-amylase, energy, Gonad, digestive gland, dsRNA, Aquatic Science, Andrology, 03 medical and health sciences, alpha-Amylase, Botany, medicine, Animals, 14. Life underwater, Gonads, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, cell-development, double-stranded-rna, ACL, RNA, temperature, biology.organism_classification, Summer mortality, Marine bivalve, tissue expression, Insect Science, 040102 fisheries, biology.protein, 0401 agriculture, forestry, and fisheries, Animal Science and Zoology, [SDE.BE]Environmental Sciences/Biodiversity and Ecology
Abstract: WOS:000355602000023; Feeding strategies and digestive capacities can have important implications for variation in energetic pathways associated with ecological and economically important traits, such as growth or reproduction in bivalve species. Here, we investigated the role of amylase in the digestive processes of Crassostrea gigas, using in vivo RNA interference. This approach also allowed us to investigate the relationship between energy intake by feeding and gametogenesis in oysters. Double-stranded (ds) RNA designed to target the two alpha-amylase genes A and B was injected in vivo into the visceral mass of oysters at two doses. These treatments caused significant reductions in mean mRNA levels of the amylase genes: -50.7% and -59% mRNA A, and -71.9% and -70.6% mRNA B in 15 and 75 mu g dsRNA-injected oysters, respectively, relative to controls. Interestingly, reproductive knock-down phenotypes were observed for both sexes at 48 days post-injection, with a significant reduction of the gonad area (-22.5% relative to controls) and germ cell under-proliferation revealed by histology. In response to the higher dose of dsRNA, we also observed reductions in amylase activity (-53%) and absorption efficiency (-5%). Based on these data, dynamic energy budget modeling showed that the limitation of energy intake by feeding that was induced by injection of amylase dsRNA was insufficient to affect gonadic development at the level observed in the present study. This finding suggests that other driving mechanisms, such as endogenous hormonal modulation, might significantly change energy allocation to reproduction, and increase the maintenance rate in oysters in response to dsRNA injection.
Published: 2015
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41. Analysis of Alternative Splicing Events in Custom Gene Datasets by AStalavista

Author: Michael Sammeth, Sylvain Foissac, Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratorio Nacional de Computação Cientifica [Rio de Janeiro] (LNCC / MCT), and Picardi E.
Subjects: 0106 biological sciences, rna processing, [SDV]Life Sciences [q-bio], Computational biology, Variation (game tree), bioinfrormatic, Biology, definition of alternative splicing, 01 natural sciences, as code, 03 medical and health sciences, Annotation, alternative splicing, [INFO]Computer Science [cs], Set (psychology), Gene, 030304 developmental biology, Genetics, 0303 health sciences, GENCODE, Event (computing), as event, splicing nomenclature, Alternative splicing, Intron, rna-seq, gene expression, transcriptome annotation, 010606 plant biology & botany
Abstract: PMID : 25577392; International audience; Alternative splicing (AS) is a eukaryotic principle to derive more than one RNA product from transcribed genes by removing distinct subsets of introns from a premature polymer. We know today that this process is highly regulated and makes up a large part of the differences between species, cell types, and states. The key to compare AS across different genes or organisms is to tokenize the AS phenomenon into atomary units, so-called AS events. These events then usually are grouped by common patterns to investigate the underlying molecular mechanisms that drive their regulation. However, attempts to decompose loci with AS observations into events are often hampered by applying a limited set of a priori defi ned event patterns which are not capable to describe all AS confi gurations and therefore cannot decompose the phenomenon exhaustively. In this chapter, we describe working scenarios of AStalavista, a computational method that reports all AS events refl ected by transcript annotations. We show how to practically employ AStalavista to study AS variation in complex transcriptomes, as characterized by the human GENCODE annotation. Our examples demonstrate how the inherent and universal AStalavista paradigm allows for an automatic delineation of AS events in custom gene datasets. Additionally, we sketch an example of an AStalavista use case including next-generation sequencing data (RNA-Seq) to enrich the landscape of discovered AS events.
Published: 2015
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42. 3‘-Substituted 7-Halogenoindirubins, a New Class of Cell Death Inducing Agents

Author: Alexios-Leandros Skaltsounis, Olivier Lozach, Laurent Meijer, Karima Bettayeb, Yoan Ferandin, Prokopios Magiatis, Panagiotis Polychronopoulos, Marina Kritsanida, Mer et santé (MS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Molécules et cibles thérapeutiques (MCT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, MESH: Cell Death, Programmed cell death, Indoles, MESH: Cell Line, Tumor, MESH: Iodine, MESH: Bromine, Antineoplastic Agents, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, MESH: Structure-Activity Relationship, Cell Line, Tumor, Drug Discovery, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Chlorine, Glycogen synthase, Protein kinase A, 030304 developmental biology, MESH: Indoles, 0303 health sciences, MESH: Humans, Cell Death, biology, 010405 organic chemistry, Effector, Chemistry, Kinase, MESH: Drug Screening Assays, Antitumor, Stereoisomerism, Fluorine, MESH: Fluorine, Bromine, MESH: Stereoisomerism, 3. Good health, 0104 chemical sciences, Biochemistry, Apoptosis, Cell culture, biology.protein, MESH: Antineoplastic Agents, Molecular Medicine, Chlorine, Drug Screening Assays, Antitumor, Signal transduction, MESH: Models, Molecular, Iodine
Abstract: Indirubins are kinase inhibitory bis-indoles that can be generated from various plant, mollusk, mammalian, and bacterial sources or chemically synthesized. We here report on the synthesis and biological evaluation of 3'-substituted 7-halogenoindirubins. Molecular modeling and kinase assays suggest that steric hindrance prevents 3'-substituted 7-halogenoindirubins from interacting with classical kinase targets of other indirubins such as cyclin-dependent kinases and glycogen synthase kinase-3. Surprisingly 3'-substituted 7-halogenoindirubins induce cell death in a diversity of human tumor cell lines. Although some 3'-substituted 7-halogenoindirubins appear to induce effector caspase-independent, nonapoptotic cell death, others trigger the landmarks of classical apoptosis. A structure-activity relationship study was performed to optimize 3'-substituted 7-halogenoindirubins with respect to solubility and cell death induction. Despite their unidentified targets, 3'-substituted 7-halogenoindirubins constitute a new promising family of antitumor agents.
Published: 2006
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43. 7-Bromoindirubin-3′-oxime induces caspase-independent cell death

Author: Jacint Boix, Karima Bettayeb, Frank Totzke, Alexios-Leandros Skaltsounis, Jan Mester, Xènia Garrofé-Ochoa, Laurent Meijer, Panos Polychronopoulos, Yoan Ferandin, Prokopios Magiatis, Judit Ribas, Marie Knockaert, Christoph Schächtele, Departament de Quimica Inorgànica, Facultat de Quimica, Universitat de Barcelona (UB), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Swine, MESH: Cell Cycle, Apoptosis, Glycogen Synthase Kinase 3, Mice, Starfish, MESH: Structure-Activity Relationship, 0302 clinical medicine, Oximes, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Tumor Suppressor Protein p53, Càncer, MESH: Swine, MESH: Glycogen Synthase Kinase 3, Cancer, MESH: Indoles, 0303 health sciences, MESH: Starfish, Cell Cycle, MESH: STAT3 Transcription Factor, MESH: Oximes, MESH: CDC2 Protein Kinase, Cyclin-Dependent Kinases, 3. Good health, Cell biology, Cell Death Process, Caspases, 030220 oncology & carcinogenesis, MESH: Cell Nucleus, Cyclin-Dependent Kinase Inhibitor p21, Recombinant Fusion Proteins, bcl-X Protein, Cysteine Proteinase Inhibitors, Spodoptera, MESH: Cyclin-Dependent Kinase Inhibitor p21, Structure-Activity Relationship, 03 medical and health sciences, MESH: Recombinant Fusion Proteins, Genetics, Humans, Molecular Biology, MESH: Humans, MESH: Caspases, MESH: Phosphorylation, MESH: Amino Acid Chloromethyl Ketones, Apoptosi, Aryl hydrocarbon receptor, MESH: Cell Line, Proteïnes quinases, MESH: Proto-Oncogene Proteins c-bcl-2, chemistry, Indirubin, MESH: Female, MESH: Cell Death, Cancer Research, Indoles, Amino Acid Chloromethyl Ketones, chemistry.chemical_compound, Protein kinases, Phosphorylation, Caspase, MESH: Spodoptera, Cell Death, biology, MESH: Cyclin-Dependent Kinases, Proto-Oncogene Proteins c-bcl-2, Biochemistry, Mort cel·lular, Quinolines, Female, Indirubins, MESH: Quinolines, STAT3 Transcription Factor, Cell death, Programmed cell death, MESH: Cell Line, Tumor, Necroptosis, Kinases, MESH: bcl-X Protein, Cell Line, MESH: Cysteine Proteinase Inhibitors, Autofàgia, Cyclin-dependent kinase, Cell Line, Tumor, CDC2 Protein Kinase, Autophagy, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Protein Kinase Inhibitors, 030304 developmental biology, Cell Nucleus, MESH: Male, MESH: Protein Processing, Post-Translational, biology.protein, Tumor Suppressor Protein p53, Protein Processing, Post-Translational
Abstract: Indirubin, an isomer of indigo, is a reported inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) as well as an agonist of the aryl hydrocarbon receptor (AhR). Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia. Numerous indirubin analogs have been synthesized to optimize this promising kinase inhibitor scaffold. We report here on the cellular effects of 7-bromoindirubin-3'-oxime (7BIO). In contrast to its 5-bromo- and 6-bromo- isomers, and to indirubin-3'-oxime, 7BIO has only a marginal inhibitory activity towards CDKs and GSK-3. Unexpectedly, 7BIO triggers a rapid cell death process distinct from apoptosis. 7-Bromoindirubin-3'-oxime induces the appearance of large pycnotic nuclei, without classical features of apoptosis such as chromatin condensation and nuclear fragmentation. 7-Bromoindirubin-3'-oxime-induced cell death is not accompanied by cytochrome c release neither by any measurable effector caspase activation. Furthermore, the death process is not altered either by the presence of Q-VD-OPh, a broad-spectrum caspase inhibitor, or the overexpression of Bcl-2 and Bcl-XL proteins. Neither AhR nor p53 is required during 7BIO-induced cell death. Thus, in contrast to previously described indirubins, 7BIO triggers the activation of non-apoptotic cell death, possibly through necroptosis or autophagy. Although their molecular targets remain to be identified, 7-substituted indirubins may constitute a new class of potential antitumor compounds that would retain their activity in cells refractory to apoptosis.
Published: 2006
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44. Using budding yeast to screen for anti-prion drugs

Author: Marc Blondel, Thibault Andrieu, Vincent Béringue, Dominique Dormont, Hervé Galons, Deborah Tribouillard, Hubert Laude, Fabienne Gug, Didier Vilette, Stéphane Bach, Nathalie Desban, Mer et santé (MS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Molécules et cibles thérapeutiques (MCT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), ProdInra, Migration, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), and École Pratique des Hautes Études (EPHE)
Subjects: Saccharomyces cerevisiae Proteins, [SDV]Life Sciences [q-bio], animal diseases, DRUG SCREENING, Computational biology, Applied Microbiology and Biotechnology, 03 medical and health sciences, 0302 clinical medicine, In vivo, 030304 developmental biology, Glutathione Peroxidase, 0303 health sciences, biology, General Medicine, biology.organism_classification, Virology, Budding yeast, Yeast, nervous system diseases, 3. Good health, Fungal prion, [SDV] Life Sciences [q-bio], Saccharomycetales, 6-AMINOPHENANTHRIDINE (6AP), Cell culture, PRIONS, YEAST-BASED ASSAYS, Molecular Medicine, Biological Assay, Protein folding, Signal transduction, NEURODEGENERATIVE DISEASES, 030217 neurology & neurosurgery, Peptide Termination Factors, Signal Transduction
Abstract: International audience; Prions are misfolded proteins capable of propagating their altered conformation which are commonly considered as the causative agent of transmissible spongiform encephalopathies, a class of fatal neurodegenerative diseases. Currently, no treatment for prion-based diseases is available. Recently we have developed a rapid, yeast-based, two-step assay to screen for anti-prion drugs [1]. This new method allowed us to identify several compounds that are effective in vivo against budding yeast [PSI+] and [URE3] prions but also able to promote mammalian prion clearance in three different cell culture-based assays. Taken together, these results validate our method as an economic and efficient high-throughput screening approach to identify novel prion inhibitors or to carry on comprehensive structure-activity studies for already isolated anti-mammalian prion drugs. These results suggest furthermore that biochemical pathways controlling prion formation and/or maintenance are conserved from yeast to human and thus amenable to pharmacological and genetic analysis. Finally, it would be very interesting to test active drugs isolated using the yeast-based assay in models for other diseases (neurodegenerative or not) involving amyloid fibers like Huntington’s, Parkinson’s or Alzheimer’s diseases.
Published: 2006
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45. Roscovitine Targets, Protein Kinases and Pyridoxal Kinase

Author: Olivier Lozach, Laurent Meijer, Sophie Schmitt, Flavio Meggio, Christoph Schächtele, Yongqin Wan, Amancio Carnero, Lin Tang, Frank Totzke, Stéphane Bach, Nathanael S. Gray, Stephen P. Coburn, Jens Reinhardt, Marcel Koken, Jean-Francois Dierick, Tao Jiang, Marie Knockaert, Lorenzo A. Pinna, Hervé Galons, Dong-Cai Liang, Blandine Baratte, Andrea S. Lerman, Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mer et santé (MS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Molécules et cibles thérapeutiques (MCT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Chinese Academy of Sciences [Beijing] (CAS), Laboratoire de Chimie Organique 2 Glycochimie (LCO2), Méthodologie de synthèse et molécules bioactives (MSMB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Padova = University of Padua (Unipd), Centro Nacional de Investigaciones Oncologicas / Spanish National Cancer Research Centre [Madrid, Espagne] (CNIO), Genomics Institute of the Novartis Research Foundation, and Novartis Research Foundation
Subjects: Models, Molecular, CDK, [SDV]Life Sciences [q-bio], Molecular Conformation, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, pharmacological selectivity, Biochemistry, Chromatography, Affinity, CLK1, Mice, chemistry.chemical_compound, Adenosine Triphosphate, 0302 clinical medicine, Tissue Distribution, Pyridoxal Kinase, Cells, Cultured, Mice, Knockout, chemistry.chemical_classification, 0303 health sciences, Molecular Structure, biology, Kinase, Cell Cycle, Pyridoxal kinase, 3. Good health, Cell biology, cyclin-dependent kinase, Pyridoxal Phosphate, 030220 oncology & carcinogenesis, Protein kinase inhibitor, Phosphorylation, Pyridoxal, Cell Survival, Molecular Sequence Data, Affinity chromatography, 03 medical and health sciences, Cyclin-dependent kinase, Roscovitine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Protein Kinase Inhibitors, Molecular Biology, Seliciclib, 030304 developmental biology, Cyclin-dependent kinase 2, Cell Biology, Fibroblasts, Protein Structure, Tertiary, Rats, Enzyme, chemistry, Purines, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, biology.protein, Protein Kinases
Abstract: International audience; Roscovitine (CYC202) is often referred to as a "selective inhibitor of cyclin-dependent kinases." Besides its use as a biological tool in cell cycle, neuronal functions, and apoptosis studies, it is currently evaluated as a potential drug to treat cancers, neurodegenerative diseases, viral infections, and glomerulonephritis. We have investigated the selectivity of (R)-roscovitine using three different methods: 1) testing on a wide panel of purified kinases that, along with previously published data, now reaches 151 kinases; 2) identifying roscovitine-binding proteins from various tissue and cell types following their affinity chromatography purification on immobilized roscovitine; 3) investigating the effects of roscovitine on cells deprived of one of its targets, CDK2. Altogether, the results show that (R)-roscovitine is rather selective for CDKs, in fact most kinases are not affected. However, it binds an unexpected, non-protein kinase target, pyridoxal kinase, the enzyme responsible for phosphorylation and activation of vitamin B 6. These results could help in interpreting the cellular actions of (R)-roscovitine but also in guiding the synthesis of more selective roscovitine analogs.
Published: 2005
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46. Epoxide-containing side chains enhance antiproliferative activity of paullones

Author: Xu Xie, Thomas Lemcke, Rick Gussio, Laurent Meijer, Maryse Leost, Daniel W. Zaharevitz, Conrad Kunick, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Indoles, Nitrile, Stereochemistry, Epoxide, Antineoplastic Agents, 010402 general chemistry, 01 natural sciences, Chemical synthesis, Kenpaullone, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, Side chain, Humans, Hydrogen peroxide, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, Biological activity, General Medicine, Benzazepines, Combinatorial chemistry, 0104 chemical sciences, Stille reaction, Human tumor, Enzyme inhibitor, biology.protein, Epoxy Compounds, Drug Screening Assays, Antitumor
Abstract: The introduction of side chains bearing epoxide motifs into the molecular scaffold of kenpaullone and 9-trifluoromethylpaullone led to improved antiproliferative activity of the novel derivatives for human tumor cell lines. The syntheses were accomplished applying Stille coupling for the introduction of unsaturated side chains into the 2-position of the paullones and subsequently employing a hydrogen peroxide/nitrile mixture for the epoxidation of C,C-double bonds.
Published: 2005
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47. Mechanism of CDK5/p25 Binding by CDK Inhibitors

Author: Marina Mapelli, Markus A. Seeliger, Andrea Musacchio, Laurent Meijer, Lucia Massimiliano, Li-Huei Tsai, Claudia Crovace, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, Indoles, Molecular Conformation, Nerve Tissue Proteins, Crystallography, X-Ray, 01 natural sciences, Serine, 03 medical and health sciences, Cyclin-dependent kinase, Oximes, Drug Discovery, Roscovitine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, Cyclin-dependent kinase 1, biology, 010405 organic chemistry, Kinase, Chemistry, Cyclin-dependent kinase 5, Cyclin-dependent kinase 2, Cyclin-Dependent Kinase 5, Stereoisomerism, Cyclin-Dependent Kinases, 3. Good health, 0104 chemical sciences, Cell biology, nervous system, Purines, biology.protein, Molecular Medicine, Phosphorylation, Cyclin-dependent kinase 6, Protein Binding
Abstract: The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 A, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.
Published: 2005
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48. Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases

Author: Alexios-Leandros Skaltsounis, Laurence H. Pearl, Paul Greengard, S Mark Roe, Andrea Musacchio, Prokopios Magiatis, Laurent Meijer, Emmanuel Mikros, Maryse Leost, Vassilios Myrianthopoulos, Panagiotis Polychronopoulos, Aldo Tarricone, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, Indoles, macromolecular substances, 01 natural sciences, Glycogen Synthase Kinase 3, Structure-Activity Relationship, 03 medical and health sciences, Cyclin-dependent kinase, GSK-3, Oximes, Drug Discovery, Structure–activity relationship, Glycogen synthase, Protein kinase A, 030304 developmental biology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Kinase, Cyclin-dependent kinase 5, Cyclin-dependent kinase 2, Cyclin-Dependent Kinases, 0104 chemical sciences, 3. Good health, Biochemistry, biology.protein, Molecular Medicine
Abstract: Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources, are potent inhibitors of several kinases, including GSK-3. Using the cocrystal structures of various indirubins with GSK-3beta, CDK2 and CDK5/p25, we have modeled the binding of indirubins within the ATP-binding pocket of these kinases. This modeling approach provided some insight into the molecular basis of indirubins' action and selectivity and allowed us to forecast some improvements of this family of bis-indoles as kinase inhibitors. Predicted molecules, including 6-substituted and 5,6-disubstituted indirubins, were synthesized and evaluated as CDK and GSK-3 inhibitors. Control, kinase-inactive indirubins were obtained by introduction of a methyl substitution on N1.
Published: 2004
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49. Evaluation and Comparison of 3D-QSAR CoMSIA Models for CDK1, CDK5, and GSK-3 Inhibition by Paullones

Author: Daniel W. Zaharevitz, Alexander Weber, C. Schultz, Rick Gussio, Flemming Jørgensen, Maryse Leost, Xu Xie, Conrad Kunick, Kathrin Lauenroth, Laurent Meijer, Thomas Lemcke, Karen Wieking, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, Quantitative structure–activity relationship, Indoles, Molecular model, Stereochemistry, Quantitative Structure-Activity Relationship, 01 natural sciences, Benzazepine, 03 medical and health sciences, chemistry.chemical_compound, CDC2 Protein Kinase, Drug Discovery, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Homology modeling, 030304 developmental biology, 0303 health sciences, biology, 010405 organic chemistry, Cyclin-Dependent Kinase 3, Rational design, Cyclin-Dependent Kinase 5, Benzazepines, Cyclin-Dependent Kinases, 0104 chemical sciences, 3. Good health, chemistry, Docking (molecular), Enzyme inhibitor, biology.protein, Lactam, Molecular Medicine, Protein Binding
Abstract: With a view to the rational design of selective GSK-3beta inhibitors, 3D-QSAR CoMSIA models were developed for the inhibition of the three serine/threonine kinases CDK1/cyclin B, CDK5/p25, and GSK-3beta by compounds from the paullone inhibitor family. The models are based on the kinase inhibition data of 52 paullone entities, which were aligned by a docking routine into the ATP-binding cleft of a CDK1/cyclin B homology model. Variation of grid spacing and column filtering were used during the optimization of the models. The predictive ability of the models was shown by a leave-one-out cross-validation and the prediction of an independent set of test compounds, which were synthesized especially for this purpose. Besides paullones with the basic indolo[3,2-d][1]benzazepine core, the test set comprised novel thieno[3',2':2,3]azepino[4,5-b]indoles, pyrido[2',3':2,3]azepino[4,5-b]indoles, and a pyrido[3',2':4,5]pyrrolo[3,2-d][1]benzazepine. The best statistical values for the CoMSIA were obtained for the CDK1-models (r(2)() = 0.929 and q(2)() = 0.699), which were clearly superior to the models for CDK5 (r(2)() = 0.874 and q(2)() = 0.652) and GSK-3 (r(2)() = 0.871 and q(2)() = 0.554).
Published: 2003
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50. Isolation of drugs active against mammalian prions using a yeast-based screening assay

Author: Thibault Andrieu, Marc Blondel, Yvette Mettey, Hervé Galons, Dominique Dormont, Nicolas Talarek, Laurent Meijer, Stéphane Bach, Jean-Michel Vierfond, Christophe Cullin, Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Immuno-Pathologie Expérimentale, Service de Neurovirologie, Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CRSSA, ManRos Therapeutics, Molécules et cibles thérapeutiques (MCT), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), and Talarek, Nicolas
Subjects: Colony Count, Microbial, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Applied Microbiology and Biotechnology, Mice, Neuroblastoma, chemistry.chemical_compound, 0302 clinical medicine, Yeasts, Protein Interaction Mapping, Microbial/methods Humans Mammals Mice Neuroblastoma Phenanthridines/*chemistry/*isolation & purification/metabolism Prions/*antagonists & inhibitors/*chemistry Protein Interaction Mapping/*methods Research Support, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], media_common, Mammals, 0303 health sciences, Phenotype, Phenanthridines, 3. Good health, Biochemistry, Molecular Medicine, Non-U.S. Gov't Saccharomyces cerevisiae/classification/*isolation & purification/*metabolism Species Specificity Yeasts/classification/isolation & purification/metabolism, Biotechnology, Animals Cell Line, Drug, Prions, media_common.quotation_subject, Biomedical Engineering, Bioengineering, Saccharomyces cerevisiae, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Species Specificity, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Tumor Colony Count, Phenanthridine, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Promoter, Yeast, In vitro, Metabolic pathway, chemistry, Cell culture, 030217 neurology & neurosurgery
Abstract: International audience; We have developed a rapid, yeast-based, two-step assay to screen for antiprion drugs. The method allowed us to identify several compounds effective against budding yeast prions responsible for the [PSI+] and [URE3] phenotypes. These inhibitors include the kastellpaolitines, a new class of compounds, and two previously known molecules, phenanthridine and 6-aminophenanthridine. Two potent promoters of mammalian prion clearance in vitro, quinacrine and chlorpromazine, which share structural similarities with the kastellpaolitines, were also active in the assay. The compounds isolated here were also active in promoting mammalian prion clearance. These results validate the present method as an efficient high-throughput screening approach to identify new prion inhibitors and furthermore suggest that biochemical pathways controlling prion formation and/or maintenance are conserved from yeast to humans.
Published: 2003
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