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9. Synthesis and evaluation of original bioisosteres of bacterial type IIA topoisomerases inhibitors

Author

Petrella, Stephanie, Aubry, Alexandra, Janvier, Genevieve, Coutant, Eloi P., Cartier, Alex, Dao, Thuy-Ha, Bonhomme, Frederic J., Motreff, Laurence, Pissis, Cedric, Bizet, Chantal, Clermont, Dominique, Begaud, Evelyne, Retailleau, Pascal, Munier-Lehmann, Helene, Capton, Estelle, Mayer, Claudine, and Janin, Yves L.

Subjects
Adenosine triphosphatase -- Analysis, Topoisomerases -- Chemical properties -- Research, Organic acids -- Analysis, Chemistry
Abstract

A recently discovered series of inhibitors of the ATPase function of bacterial type IIA topoisomerases featuring a carboxypyrrole component led us to attempt to replace this group with a potentially bioisosteric carboxypyrazole. Accordingly, synthetic pathways to 2-(4-(1H-pyrazole-5-carboxamido)piperidin-1-yl)thiazole-5-carboxylic acids or 2-(4-(N-methyl-1H-pyrazole5-carboxamido)piperidin-1-yl)thiazole-5-carboxylic acids featuring an array of substituents on the pyrazole ring were explored. Unfortunately, none of the analogues made were effective on the ATPase function of Mycobacterium tuberculosis gyrase as well on the DNA supercoiling activity of the whole gyrase of M. tuberculosis and Escherichia coli. However, this work is still providing original insights in chemistry as well as in the structure-activity relationships of this series of inhibitors. Key words: bacterial type IIA topoisomerases, bioisosteres, 3-pyrazole carboxylic acid. Une serie recente d'inhibiteurs de la fonction ATP-asique des topoisomerases bacteriennes de type IIA comportant un noyau carboxypyrrole nous a conduits a tenter de remplacer celui-ci par un noyau carboxypyrazole bioisostere. Ainsi, des acces aux derives d'acide 2-(4-(1H-pyrazole-5-carboxamido)piperidin-1-yl)thiazole-5-carboxylique, comportant une gamme de substituants, ont ete explores. Malheureusement, aucun des analogues prepares n'a eu d'effet, que ce soit sur la fonction ATP-asique de la gyrase de Mycobacterium tuberculosis ou sur l'activite de surenroulement des gyrases de M. tuberculosis ou d'Escherichia coli. Toutefois, ce travail represente une contribution originale en ce qui concerne la chimie ou les relations structure-activite de cette serie d'inhibiteurs. Mots-cles: ATPase, topoisomerases, antibiotic, bioisosteres, pyrazole., Introduction In the recent past, the strategies used to find new antibiotics effective on bacterial strains such as multiple resistant Mycobacterium tuberculosis, the Gram-positive methicillin-resistant strains of Staphylococcus aureus, and [...]

Published
2016
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12. Lipophilic quinolone derivatives: Synthesis and in vitro antibacterial evaluation

Author

Sadowski, Elodie, Bercot, Beatrice, Chauffour, Aurélie, Gomez, Catherine, Varon, Emmanuelle, Mainardis, Mary, Sougakoff, Wladimir, Mayer, Claudine, Sachon, Emmanuelle, Anquetin, Guillaume, Aubry, Alexandra, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Génomique, bioinformatique et chimie moléculaire (GBCM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre Hospitalier Intercommunal de Créteil (CHIC), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Spectrométrie de masse de Sorbonne Université [IBPS] (MS3U), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Interfaces, Traitements, Organisation et Dynamique des Systèmes (ITODYS (UMR_7086)), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), The work was supported by grants from the order of Malta Grants for Leprosy Research, QUIET Lutech MA077/SL00091 – ref UPMCX13042 from the SATT LUTECH and ANR DETONATOR., ANR-20-CE18-0030,DETONATOR,Décryptage du mode d'action de nouveaux antituberculeux prometteurs(2020), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Service de Bactériologie et d'Hygiène Hospitalière [CHU Pitié-Salpêtrière], Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-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 de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), Noel, Anne-Laure, Décryptage du mode d'action de nouveaux antituberculeux prometteurs - - DETONATOR2020 - ANR-20-CE18-0030 - AAPG2020 - VALID, and Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière] (CNR-MyRMA)

Subjects
Dose-Response Relationship, Drug, Molecular Structure, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, ESKAPE, Microbial Sensitivity Tests, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Quinolones, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Neisseria gonorrhoeae, Anti-Bacterial Agents, Antibacterial, Structure-Activity Relationship, Synthesis, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Hydrophobic and Hydrophilic Interactions, Fluoroquinolones
Abstract

International audience; This paper reports on the design of a series of 10 novel lipophilic piperazinyl derivatives of the 1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, their synthesis, their characterisation by 1H, 13C and 19F NMR, IR spectroscopy and HRMS, as well as their biological activity against bacteria of medical interest. Among these derivatives, 2 were as potent as the parent quinolone against Neisseriagonorrhoeae whereas all the compounds displayed lower activity than the parent quinolone against other bacteria of medical interest. Our results showing that the increased lipophilicity was deleterious for antibacterial activity may help to design new quinolone derivatives in the future, especially lipophilic quinolones which have been poorly investigated previously.

Published
2022
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17. Crl binds to domain 2 of [sigma]s and confers a competitive advantage on a natural rpoS mutant of Salmonella enterica serovar Typhi

Author

Monteil, Veronique, Kolb, Annie, Mayer, Claudine, Hoos, Sylviane, England, Patrick, and Norel, Francoise

Subjects
Salmonella -- Genetic aspects, Salmonella -- Physiological aspects, Protein binding -- Research, Bacterial proteins -- Physiological aspects, Bacterial proteins -- Genetic aspects, Biological sciences
Abstract

The RpoS sigma factor ([[sigma].sup.S]) is the master regulator of the bacterial response to a variety of stresses. Mutants in rpoS arise in bacterial populations in the absence of stress, probably as a consequence of a subtle balance between self-preservation and nutritional competence. We characterized here one natural rpoS mutant of Salmonella enterica serovar Typhi (Ty19). We show that the rpoS allele of Ty19 ([rpoS.sub.Ty19]) led to the synthesis of a [[sigma].sup.S.sub.Ty19] protein carrying a single glycine-to-valine substitution at position 282 in [[sigma].sup.S] domain 4, which was much more dependent than the wild-type [[sigma].sup.S] protein on activation by Crl, a chaperone-like protein that increases the affinity of [[sigma].sup.S] for the RNA polymerase core enzyme (E). We used the bacterial adenylate cyclase two-hybrid system to demonstrate that Crl bound to residues 72 to 167 of [[sigma].sup.S] domain 2 and that G282V substitution did not directly affect Crl binding. However, this substitution drastically reduced the ability of [[sigma].sup.S.sub.Ty19] to bind E in a surface plasmon resonance assay, a defect partially rescued by Crl. The modeled structure of the E[[sigma].sup.S] holoenzyme suggested that substitution G282V could directly disrupt a favorable interaction between [[sigma].sup.S] and E. The [rpOS.sub.Ty19] allele conferred a competitive fitness when the bacterial population was wild type for crl but was outcompeted in [DELTA]crl populations. Thus, these results indicate that the competitive advantage of the [rpoS.sub.Ty19] mutant is dependent on Crl and suggest that crl plays a role in the appearance of rpoS mutants in bacterial populations. doi: 10.1128/JB.00801-10

Published
2010

19. Structure-based site-directed mutagenesis of the UDP-MurNAc-pentapeptide-binding cavity of the FemX alanyl transferase from Weissella viridescens

Author

Maillard, Antoine P., Biarrotte-Sorin, Sabrina, Villet, Regis, Mesnage, Stephane, Bouhss, Ahmed, Wladimir, Sougakoff, Mayer, Claudine, and Arthur, Michel

Subjects
Bacterial proteins -- Research, Transfer RNA -- Research, Biological sciences
Abstract

Weissella viridescens FemX (Fem[X.sub.Wv] belongs to the Fern family of nonribosomal peptidyl transferases that use aminoacyl-tRNA as the amino acid donor to synthesize the peptide cross-bridge found in the peptidoglycan of many species of pathogenic gram-positive bacteria. We have recently solved the crystal structure of [FemX.sub.Wv] in complex with the peptidoglycan precursor UDP-MurNAc-pentapeptide and report here the site-directed mutagenesis of nine residues located in the binding cavity for this substrate. Two substitutions, Lys36Met and Arg211Met, depressed Fem[X.sub.Wv] transferase activity below detectable levels without affecting protein folding. Analogues of UDP-MurNAc-pentapeptide lacking the phosphate groups or the C-terminal D-alanyl residues were not substrates of the enzyme. These results indicate that Lys36 and Arg211 participate in a complex hydrogen bond network that connects the C-terminal D-Ala residues to the phosphate groups of UDP-MurNAc-pentapeptide and constrains the substrate in a conformation that is essential for transferase activity.

Published
2005

33. X-Ray Diffraction in Biology : How Can We See Dna and Proteins in Three Dimensions?

Author

Mayer, Claudine

Subjects
Technology & Engineering / Electronics / Optoelectronics
Abstract

Knowing the three-dimensional structure of biological macromolecules, such as proteins and DNA, is crucial for understanding the functioning of life. Biological crystallography, the main method of structural biology, which is the branch of biology that studies the structure and spatial organization in biological macromolecules, is based on the study of X-ray diffraction by crystals of macromolecules. This article will present the principle, methodology and limitations of solving biological structures by crystallography.

Published
2017

34. The stress sigma factor of RNA polymerase RpoS/σS is a solvent-exposed open molecule in solution

Author

Cavaliere, Paola, primary, Brier, Sébastien, additional, Filipenko, Petr, additional, Sizun, Christina, additional, Raynal, Bertrand, additional, Bonneté, Françoise, additional, Levi-Acobas, Fabienne, additional, Bellalou, Jacques, additional, England, Patrick, additional, Chamot-Rooke, Julia, additional, Mayer, Claudine, additional, and Norel, Françoise, additional

Published
2018
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36. The archaeal homolog of the Imp4 protein, a eukaryotic U3 snoRNP component

Author

Mayer, Claudine, Suck, Dietrich, and Poch, Olivier

Subjects
Proteins -- Physiological aspects, Eukaryotic cells -- Physiological aspects, RNA -- Physiological aspects, Biological sciences, Chemistry
Abstract

Homologs of the Imp4 protein, a component specific to the eukaryotic U3 snoRNP complex, have been found in all archaeal genomes. The archaeal and eukaryotic Imp4 proteins that are related to four other protein families, the Imp4-like, the SSF1 homologs and two sets of hypothetical proteins, are characterized by the Imp4 signature pattern. These findings, together with the presence of other snoRNPs homologs in Archaea, provide evidence for similar RNA processing and folding in Eukarya and Archaea.

Published
2001

37. Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy

Author

Méjécase, Cécile, primary, Laurent-Coriat, Caroline, additional, Mayer, Claudine, additional, Poch, Olivier, additional, Mohand-Saïd, Saddek, additional, Prévot, Camille, additional, Antonio, Aline, additional, Boyard, Fiona, additional, Condroyer, Christel, additional, Michiels, Christelle, additional, Blanchard, Steven, additional, Letexier, Mélanie, additional, Saraiva, Jean-Paul, additional, Sahel, José-Alain, additional, Audo, Isabelle, additional, and Zeitz, Christina, additional

Published
2016
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39. The stress sigma factor of RNA polymerase RpoS/ σS is a solvent-exposed open molecule in solution.

Author

Cavaliere, Paola, Brier, Sébastien, Filipenko, Petr, Sizun, Christina, Raynal, Bertrand, Bonneté, Françoise, Levi-Acobas, Fabienne, Bellalou, Jacques, England, Patrick, Chamot-Rooke, Julia, Mayer, Claudine, and Norel, Françoise

Subjects
RNA polymerases, DNA-binding proteins, DEUTERIUM, MASS spectrometry, GENE expression
Abstract

In bacteria, one primary and multiple alternative sigma (σ) factors associate with the RNA polymerase core enzyme (E) to form holoenzymes (Eσ) with different promoter recognition specificities. The alternative σ factor RpoS/σS is produced in stationary phase and under stress conditions and reprograms global gene expression to promote bacterial survival. To date, the three-dimensional structure of a full-length free σ factor remains elusive. The current model suggests that extensive interdomain contacts in a free σ factor result in a compact conformation that masks the DNA-binding determinants of σ, explaining why a free σ factor does not bind double-stranded promoter DNA efficiently. Here, we explored the solution conformation of σS using amide hydrogen/deuterium exchange coupled with mass spectrometry, NMR, analytical ultracentrifugation and molecular dynamics. Our data strongly argue against a compact conformation of free σS. Instead, we show that σS adopts an open conformation in solution in which the folded σ2 and σ4 domains are interspersed by domains with a high degree of disorder. These findings suggest that E binding induces major changes in both the folding and domain arrangement of σS and provide insights into the possible mechanisms of regulation of σS activity by its chaperone Crl. [ABSTRACT FROM AUTHOR]

Published
2018
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42. Specificity of L,D-transpeptidases from gram-positive bacteria producing different peptidoglycan chemotypes

Author

Magnet, Sophie, Arbeloa, Ana, Mainardi, Jean-Luc, Hugonnet, Jean-Emmanuel, Fourgeaud, Martine, Dubost, Lionel, Marie, Arul, Delfosse, Vanessa, Mayer, Claudine, Rice, Louis, Arthur, Michel, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, and ACI Microbiologie 2003' from the Fonds National de la Science (Grant ACIM-4-9), the European Community (COBRA, contract LSHM-CT-2003-503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale.

Subjects
MESH: Enterococcus faecalis, MESH: Penicillin-Binding Proteins, MESH: Peptidyl Transferases, MESH: Sequence Homology, Amino Acid, MESH: Peptidoglycan, MESH: Bacillus subtilis, MESH: Cell Wall, MESH: Drug Resistance, Bacterial, MESH: Oligopeptides, MESH: Species Specificity, MESH: Diaminopimelic Acid, MESH: Substrate Specificity, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Bacterial Proteins, MESH: Cysteine Endopeptidases
Abstract

International audience; We report here the first direct assessment of the specificity of a class of peptidoglycan cross-linking enzymes, the L,D-transpeptidases, for the highly diverse structure of peptidoglycan precursors of Gram-positive bacteria. The lone functionally characterized member of this new family of active site cysteine peptidases, Ldt(fm) from Enterococcus faecium, was previously shown to bypass the D,D-transpeptidase activity of the classical penicillin-binding proteins leading to high level cross-resistance to glycopeptide and beta-lactam antibiotics. Ldt(fm) homologues from Bacillus subtilis (Ldt(Bs)) and E. faecalis (Ldt(fs)) were found here to cross-link their cognate disaccharide-peptide subunits containing meso-diaminopimelic acid (mesoDAP(3)) and L-Lys(3)-L-Ala-L-Ala at the third position of the stem peptide, respectively, instead of L-Lys(3)-d-iAsn in E. faecium. Ldt(fs) differed from Ldt(fm) and Ldt(Bs) by its capacity to hydrolyze the L-Lys(3)-D-Ala(4) bond of tetrapeptide (L,D-carboxypeptidase activity) and pentapeptide (L,D-endopeptidase activity) stems, in addition to the common cross-linking activity. The three enzymes were specific for their cognate acyl acceptors in the cross-linking reaction. In contrast to Ldt(fs), which was also specific for its cognate acyl donor, Ldt(fm) tolerated substitution of L-Lys(3)-D-iAsn by L-Lys(3)-L-Ala-L-Ala. Likewise, Ldt(Bs) tolerated substitution of mesoDAP(3) by L-Lys(3)-D-iAsn and L-Lys(3)-L-Ala-L-Ala in the acyl donor. Thus, diversification of the structure of peptidoglycan precursors associated with speciation has led to a parallel evolution of the substrate specificity of the L,D-transpeptidases affecting mainly the recognition of the acyl acceptor. Blocking the assembly of the side chain could therefore be used to combat antibiotic resistance involving L,D-transpeptidases.

Published
2007
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43. L,D-transpeptidation in Gram-positive Bacteria

Author

Magnet, Sophie, Arbeloa, Ana, Mainardi, Jean-Luc, Hugonnet, Jean-Emmanuel, Fourgeaud, Martine, Dubost, Lionel, Marie, Arul, Delfosse, Vanessa, Mayer, Claudine, Rice, Louis, Arthur, Michel, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, ACI Microbiologie 2003' from the Fonds National de la Science (Grant ACIM-4-9), the European Community (COBRA, contract LSHM-CT-2003-503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale., and Lecerf, Maxime

Subjects
MESH: Enterococcus faecalis, MESH: Penicillin-Binding Proteins, MESH: Peptidyl Transferases, MESH: Sequence Homology, Amino Acid, MESH: Peptidoglycan, MESH: Bacillus subtilis, MESH: Cell Wall, MESH: Drug Resistance, Bacterial, MESH: Oligopeptides, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Species Specificity, MESH: Diaminopimelic Acid, MESH: Substrate Specificity, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Bacterial Proteins, MESH: Cysteine Endopeptidases
Abstract

International audience; We report here the first direct assessment of the specificity of a class of peptidoglycan cross-linking enzymes, the L,D-transpeptidases, for the highly diverse structure of peptidoglycan precursors of Gram-positive bacteria. The lone functionally characterized member of this new family of active site cysteine peptidases, Ldt(fm) from Enterococcus faecium, was previously shown to bypass the D,D-transpeptidase activity of the classical penicillin-binding proteins leading to high level cross-resistance to glycopeptide and beta-lactam antibiotics. Ldt(fm) homologues from Bacillus subtilis (Ldt(Bs)) and E. faecalis (Ldt(fs)) were found here to cross-link their cognate disaccharide-peptide subunits containing meso-diaminopimelic acid (mesoDAP(3)) and L-Lys(3)-L-Ala-L-Ala at the third position of the stem peptide, respectively, instead of L-Lys(3)-d-iAsn in E. faecium. Ldt(fs) differed from Ldt(fm) and Ldt(Bs) by its capacity to hydrolyze the L-Lys(3)-D-Ala(4) bond of tetrapeptide (L,D-carboxypeptidase activity) and pentapeptide (L,D-endopeptidase activity) stems, in addition to the common cross-linking activity. The three enzymes were specific for their cognate acyl acceptors in the cross-linking reaction. In contrast to Ldt(fs), which was also specific for its cognate acyl donor, Ldt(fm) tolerated substitution of L-Lys(3)-D-iAsn by L-Lys(3)-L-Ala-L-Ala. Likewise, Ldt(Bs) tolerated substitution of mesoDAP(3) by L-Lys(3)-D-iAsn and L-Lys(3)-L-Ala-L-Ala in the acyl donor. Thus, diversification of the structure of peptidoglycan precursors associated with speciation has led to a parallel evolution of the substrate specificity of the L,D-transpeptidases affecting mainly the recognition of the acyl acceptor. Blocking the assembly of the side chain could therefore be used to combat antibiotic resistance involving L,D-transpeptidases.

Published
2007
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44. Structural and functional features of Crl proteins and identification of conserved surface residues required for interaction with the RpoS/σS subunit of RNA polymerase

Author

Cavaliere, Paola, primary, Levi-Acobas, Fabienne, additional, Mayer, Claudine, additional, Saul, Frederick A., additional, England, Patrick, additional, Weber, Patrick, additional, Raynal, Bertrand, additional, Monteil, Véronique, additional, Bellalou, Jacques, additional, Haouz, Ahmed, additional, and Norel, Françoise, additional

Published
2014
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49. The Structure of FemXWv in Complex with a Peptidyl‐RNA Conjugate: Mechanism of Aminoacyl Transfer from Ala‐tRNAAla to Peptidoglycan Precursors

Author

Fonvielle, Matthieu, primary, Li de La Sierra‐Gallay, Inés, additional, El‐Sagheer, Afaf H., additional, Lecerf, Maxime, additional, Patin, Delphine, additional, Mellal, Dénia, additional, Mayer, Claudine, additional, Blanot, Didier, additional, Gale, Nittaya, additional, Brown, Tom, additional, van Tilbeurgh, Herman, additional, Ethève‐Quelquejeu, Mélanie, additional, and Arthur, Michel, additional

Published
2013
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