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1. The Polyamine Spermidine Modulates the Production of the Bacterial Genotoxin Colibactin

Author

Camille V. Chagneau, Christophe Garcie, Nadège Bossuet-Greif, Sophie Tronnet, Alexander O. Brachmann, Jörn Piel, Jean-Philippe Nougayrède, Patricia Martin, and Eric Oswald

Subjects
Escherichia coli, biosynthesis, colorectal cancer, genotoxic colibactin, polyamines, Microbiology, QR1-502
Abstract

ABSTRACT Colibactin is a polyketide/nonribosomal peptide produced by Escherichia coli strains that harbor the pks island. This toxin induces DNA double-strand breaks and DNA interstrand cross-links in infected eukaryotic cells. Colibactin-producing strains are found associated with colorectal cancer biopsy specimens and promote intestinal tumor progression in various murine models. Polyamines are small polycationic molecules produced by both microorganisms and eukaryotic cells. Their levels are increased in malignancies, where they contribute to disease progression and metastasis. In this study, we demonstrated that the endogenous spermidine synthase SpeE is required for full genotoxic activity of colibactin-producing E. coli. Supplying spermidine in a ΔspeE pks+ E. coli strain restored genotoxic activity. Spermidine is involved in the autotoxicity linked to colibactin and is required for direct damaging activity on DNA. The production of the colibactin prodrug motif is impaired in ΔspeE mutants. Therefore, we demonstrated that spermidine has a direct impact on colibactin synthesis. IMPORTANCE Colibactin-producing Escherichia coli strains are associated with cancerous and precancerous colorectal tissues and are suspected of promoting colorectal carcinogenesis. In this study, we describe a new interplay between the synthesis of the genotoxin colibactin and the polyamine spermidine. Polyamines are highly abundant in cancer tissue and are associated with cell proliferation. The need for spermidine in genotoxic activity provides a new perspective on the role of these metabolites in the pathogenicity of colibactin-producing E. coli strains in colorectal cancer.

Published
2019
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2. Interplay between siderophores and colibactin genotoxin biosynthetic pathways in Escherichia coli.

Author

Patricia Martin, Ingrid Marcq, Giuseppe Magistro, Marie Penary, Christophe Garcie, Delphine Payros, Michèle Boury, Maïwenn Olier, Jean-Philippe Nougayrède, Marc Audebert, Christian Chalut, Sören Schubert, and Eric Oswald

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

In Escherichia coli, the biosynthetic pathways of several small iron-scavenging molecules known as siderophores (enterobactin, salmochelins and yersiniabactin) and of a genotoxin (colibactin) are known to require a 4'-phosphopantetheinyl transferase (PPTase). Only two PPTases have been clearly identified: EntD and ClbA. The gene coding for EntD is part of the core genome of E. coli, whereas ClbA is encoded on the pks pathogenicity island which codes for colibactin. Interestingly, the pks island is physically associated with the high pathogenicity island (HPI) in a subset of highly virulent E. coli strains. The HPI carries the gene cluster required for yersiniabactin synthesis except for a gene coding its cognate PPTase. Here we investigated a potential interplay between the synthesis pathways leading to the production of siderophores and colibactin, through a functional interchangeability between EntD and ClbA. We demonstrated that ClbA could contribute to siderophores synthesis. Inactivation of both entD and clbA abolished the virulence of extra-intestinal pathogenic E. coli (ExPEC) in a mouse sepsis model, and the presence of either functional EntD or ClbA was required for the survival of ExPEC in vivo. This is the first report demonstrating a connection between multiple phosphopantetheinyl-requiring pathways leading to the biosynthesis of functionally distinct secondary metabolites in a given microorganism. Therefore, we hypothesize that the strict association of the pks island with HPI has been selected in highly virulent E. coli because ClbA is a promiscuous PPTase that can contribute to the synthesis of both the genotoxin and siderophores. The data highlight the complex regulatory interaction of various virulence features with different functions. The identification of key points of these networks is not only essential to the understanding of ExPEC virulence but also an attractive and promising target for the development of anti-virulence therapy strategies.

Published
2013
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3. Interplay Between Siderophores and Colibactin Genotoxin in Escherichia coli

Author

Sophie Tronnet, Eric Oswald, Christophe Garcie, Patricia Martin, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Bactériologie-Hygiène, Centre Hospitalier Universitaire de Toulouse, Agence Nationale de la Recherche (France) [grant ANR-13-BSV3-0015-02, ANR-13-BSV1-0028-01], INCA-PLBIO13-123., ANR-13-BSV3-0015,RESTRICTIRON,Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte(2013), ANR-13-BSV1-0028,Coliforlife,Répercussions de la colonisation néonatale par Escherichia coli au sein du microbiote intestinal sur la susceptibilité à développer des pathologies immunes.(2013), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Service Bactériologie et hygiène [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ProdInra, Migration, Blanc 2013 - Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte - - RESTRICTIRON2013 - ANR-13-BSV3-0015 - Blanc 2013 - VALID, and Blanc 2013 - Répercussions de la colonisation néonatale par Escherichia coli au sein du microbiote intestinal sur la susceptibilité à développer des pathologies immunes. - - Coliforlife2013 - ANR-13-BSV1-0028 - Blanc 2013 - VALID

Subjects
0301 basic medicine, Siderophore, commensalism, Virulence Factors, Anemia, [SDV]Life Sciences [q-bio], 030106 microbiology, Clinical Biochemistry, Siderophores, Virulence, Biology, medicine.disease_cause, Biochemistry, Enterobactin, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, iron, Bacterial Proteins, Bacteriocins, Escherichia coli, Genetics, medicine, Homeostasis, Humans, Molecular Biology, Heme, Phylogeny, 2. Zero hunger, pathogenesis, E. coli, Gene Expression Regulation, Bacterial, Cell Biology, Iron deficiency, Commensalism, medicine.disease, Antimicrobial, Gastrointestinal Microbiome, 3. Good health, Repressor Proteins, [SDV] Life Sciences [q-bio], chemistry, Polyketides, Dietary Supplements, Peptides
Abstract

Highly pathogenic Escherichia coli strains that belong to the phylogenetic group B2 have developed a greater ability to acquire iron (heme receptor and numerous siderophores), to produce the genotoxin colibactin and to synthesize antimicrobial siderophore-microcins. There is an increased prevalence of these E. coli strains over the last 30 years in the intestinal microbiota in industrialized countries. Integrating the regulation of fitness/virulence factors, such as siderophores, colibactin and siderophore-microcins into networks that respond to specific environmental signals, such as the local iron concentration, could result in an accurate production of specific fitness/virulence factors, so that the E. coli can adapt to the competitive environment that is the gut and/or the blood. Iron deficiency is common in infancy, even in industrialized countries. Usual strategies for anemia correction are iron supplementation and iron fortification of foods. The long-term consequences and risks associated with high iron supply in the light of this iron-dependent network described in this review could explain at least in part the increased prevalence of E. coli B2 in the gut of people in industrialized countries. © 2017 IUBMB Life, 69(6):435-441, 2017.

Published
2017
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4. High iron supply inhibits the synthesis of the genotoxin colibactin by pathogenic Escherichia coli through a non-canonical Fur/RyhB-mediated pathway

Author

Alexander O. Brachmann, Eric Oswald, Christophe Garcie, Sophie Tronnet, Patricia Martin, Jörn Piel, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut de Recherche en Santé Digestive (IRSD ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Bactériologie-Hygiène, Centre Hospitalier Universitaire de Toulouse, Institute of Microbiology, Université de Lausanne (UNIL), Agence Nationale de la Recherche (France) [grant ANR-13-BSV3-0015-02, ANR-13-BSV1-0028-01], ANR-13-BSV3-0015,RESTRICTIRON,Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte(2013), ANR-13-BSV1-0028,Coliforlife,Répercussions de la colonisation néonatale par Escherichia coli au sein du microbiote intestinal sur la susceptibilité à développer des pathologies immunes.(2013), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT)

Subjects
0301 basic medicine, Transcription, Genetic, Transferases (Other Substituted Phosphate Groups), microbiote digestif, medicine.disease_cause, RyhB, fer, chemistry.chemical_compound, iron, Pathogenic Escherichia coli, Transcription (biology), Immunology and Allergy, Iron, Colibactin, Fur, Virulence, biology, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 6. Clean water, 3. Good health, RNA, Bacterial, Infectious Diseases, Endocrinologie et métabolisme, escherichia coli, Signal Transduction, Microbiology (medical), 030106 microbiology, entérobactérie, Microbiology, 03 medical and health sciences, Bacterial Proteins, Biosynthesis, Spheroids, Cellular, medicine, Humans, Escherichia coli, Endocrinology and metabolism, General Immunology and Microbiology, Wild type, RNA, Gene Expression Regulation, Bacterial, biology.organism_classification, colibactin, Repressor Proteins, 030104 developmental biology, chemistry, Polyketides, RNA, Small Untranslated, Peptides, Carcinogenesis, Gene Deletion, HeLa Cells, Mutagens
Abstract

Pathogens and Disease, 75 (5), ISSN:2049-632X

Published
2017
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5. The bacterial stress-responsive Hsp90 chaperone is required for the production of the genotoxin colibactin and the siderophore yersiniabactin by Escherichia coli

Author

Alexander O. Brachmann, Jörn Piel, Alex J. McCarthy, Sébastien Houle, Eric Oswald, Christophe Garcie, Jean-Philippe Nougayrède, Pierre Genevaux, Peter W. Taylor, Amélie Garénaux, Patricia Martin, Sophie Tronnet, Marie Penary, Charles M. Dozois, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), University College of London [London] (UCL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Laboratoire de microbiologie et génétique moléculaires - UMR5100 (LMGM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Bactériologie-Hygiène [Toulouse], This work was supported by the Agence Nationale de la Recherche (France) [grants ANR-13-BSV3-0015-02 and ANR-13-BSV1-0028-01], by the Medical Research Council (UK) [grant MR/K018396/1 to A.J.M.], and by the Natural Sciences and Engineering Research Council (Canada) [Discovery grant to C.M.D.], ANR-13-BSV3-0015,RESTRICTIRON,Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte(2013), ANR-13-BSV1-0028,Coliforlife,Répercussions de la colonisation néonatale par Escherichia coli au sein du microbiote intestinal sur la susceptibilité à développer des pathologies immunes.(2013), Courcelles, Michel, Blanc 2013 - Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte - - RESTRICTIRON2013 - ANR-13-BSV3-0015 - Blanc 2013 - VALID, Blanc 2013 - Répercussions de la colonisation néonatale par Escherichia coli au sein du microbiote intestinal sur la susceptibilité à développer des pathologies immunes. - - Coliforlife2013 - ANR-13-BSV1-0028 - Blanc 2013 - VALID, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Laboratoire de microbiologie et génétique moléculaires (LMGM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], medicine.disease_cause, Yersiniabactin, chemistry.chemical_compound, Protein Interaction Mapping, Immunology and Allergy, Escherichia coli Infections, chemistry.chemical_classification, biology, Escherichia coli Proteins, yersiniabactin, meningitis, Endopeptidase Clp, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Biochemistry, Female, colibactin, Virulence, Hsp90, Microbiology, 03 medical and health sciences, Polyketide, Phenols, Nonribosomal peptide, Heat shock protein, medicine, Escherichia coli, Animals, HSP90 Heat-Shock Proteins, Rats, Wistar, siderophores, stress response, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Pathogenicity island, Mice, Inbred C57BL, virulence, Disease Models, Animal, Thiazoles, 030104 developmental biology, chemistry, Polyketides, Chaperone (protein), heat shock proteins, biology.protein, HtpG, Peptides, Gene Deletion, Mutagens
Abstract

International audience; The genotoxin colibactin synthesized by Escherichia coli is a secondary metabolite belonging to the chemical family of hybrid polyketide/non-ribosomal peptide compounds. It is produced by a complex biosynthetic assembly line encoded by the pks pathogenicity island. The presence of this large cluster of genes in the E. coli genome is invariably associated with the High-Pathogenicity Island, encoding the siderophore yersiniabactin that belongs to the same chemical family as colibactin. The E. coli heat shock protein HtpG (Hsp90Ec) is the bacterial homolog of the eukaryotic molecular chaperone Hsp90 involved in the protection of cellular proteins against a variety of environmental stresses. In contrast to the eukaryotic Hsp90, the functions and client proteins of Hsp90Ec are poorly known. Here, we demonstrated that production of colibactin and yersiniabactin is abolished in the absence of Hsp90Ec We further characterized an interplay between the Hsp90Ec molecular chaperone and the ClpQ protease involved in colibactin and yersiniabactin synthesis. Finally, we demonstrated that Hsp90Ec is required for the full in vivo virulence of extraintestinal pathogenic E. coli This is the first report highlighting the role of heat shock protein Hps90Ec in the production of two secondary metabolites involved in E. coli virulence

Published
2016
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6. Iron Homeostasis Regulates the Genotoxicity of Escherichia coli That Produces Colibactin

Author

Sophie Tronnet, Christophe Garcie, Patricia Martin, Nadine Rehm, Eric Oswald, Ulrich Dobrindt, ProdInra, Archive Ouverte, Blanc 2013 - Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte - - RESTRICTIRON2013 - ANR-13-BSV3-0015 - Blanc 2013 - VALID, Blanc 2013 - Répercussions de la colonisation néonatale par Escherichia coli au sein du microbiote intestinal sur la susceptibilité à développer des pathologies immunes. - - Coliforlife2013 - ANR-13-BSV1-0028 - Blanc 2013 - VALID, UMR 1220, École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Bactériologie-Hygiène, Institute of Hygiene, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Interdisciplinary Center for Clinical Research (IZKF), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), ANR [ANR-13-BSV3-0015-02, ANR-13-BSV1-0028-01], INCA [INCA-PLBIO13-123], IZKF [Dob2/013/12], ANR-13-BSV3-0015,RESTRICTIRON,Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte(2013), ANR-13-BSV1-0028,Coliforlife,Répercussions de la colonisation néonatale par Escherichia coli au sein du microbiote intestinal sur la susceptibilité à développer des pathologies immunes.(2013), Oswald, Eric, Martin, Patricia, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), UMR 1416, INRA Transfert, Università Cattolica del Sacro Cuore [Roma] (Unicatt), University of Münster, and Università cattolica del Sacro Cuore [Roma] (Unicatt)

Subjects
0301 basic medicine, Siderophore, Iron, [SDV]Life Sciences [q-bio], 030106 microbiology, Immunology, homéostasie du fer, entérobactérie, Biology, medicine.disease_cause, Microbiology, Virulence factor, RyhB, 03 medical and health sciences, Bacterial Proteins, Transcription (biology), Transcriptional regulation, medicine, Homeostasis, Escherichia coli, Regulation of gene expression, virulence bactérienne, Base Sequence, genotoxicity, RNA, Gene Expression Regulation, Bacterial, Molecular Pathogenesis, [SDV] Life Sciences [q-bio], RNA, Bacterial, Infectious Diseases, Biochemistry, Polyketides, génotoxicité, Parasitology, escherichia coli, Peptides
Abstract

The genotoxin colibactin is a secondary metabolite produced by a variety of pathogenic enterobacteria. Its biosynthesis requires the enzymatic activity of the phosphopantetheinyl transferase (PPTase) ClbA. We previously showed that ClbA can also contribute to the production of siderophores. Because the biosynthesis of siderophores is regulated by iron availability, we hypothesized that iron could also modulate the production of colibactin through the transcriptional regulation of clbA . This study revealed an increased transcription of clbA under iron-limiting conditions and a decrease of clbA expression in iron-rich media. We demonstrate that clbA transcription is regulated by both the ferric uptake regulator (Fur) and the small regulatory noncoding RNA RyhB. We evidenced that the regulation of the transcription of clbA by Fur and RyhB leads to the regulation of colibactin production. This work highlights the complex mechanism of regulation of an important virulence factor by the two major regulators of bacterial iron homeostasis, making iron a key environmental factor contributing to bacterial virulence and carcinogenesis.

Published
2016
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7. Colibactin biosynthesis and biological activity depend on the rare aminomalonyl polyketide precursor

Author

Jörn Piel, Reiko Ueoka, Patricia Martin, Christophe Garcie, Vincen Wu, Alexander O. Brachmann, Eric Oswald, Institute of Microbiology, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), 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), CHU Toulouse [Toulouse], Centre de Physiopathologie de Toulouse-Purpan (INSERM U563 - CNRS UMR1037), CHU Toulouse [Toulouse]-Institut Claudius Regaud-Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de lutte contre le cancer (CLCC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
DNA damage, Metabolite, [SDV]Life Sciences [q-bio], medicine.disease_cause, Catalysis, Polyketide, chemistry.chemical_compound, Biosynthesis, Colibactin, Materials Chemistry, medicine, Escherichia coli, Escherichia coli Proteins, Metals and Alloys, Biological activity, General Chemistry, 3. Good health, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Biochemistry, chemistry, Polyketides, Mutation, Ceramics and Composites, Carcinogenesis, Peptides
Abstract

International audience; The as-yet unidentified E. coli metabolite colibactin induces DNA damage in eukaryotic cells and promotes tumorigenesis. Its wide distribution in pathogenic and probiotic strains has raised great interest in its structure and biosynthesis. Here we show that colibactin formation involves a rare aminomalonyl unit used as a building block.

Published
2015
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8. Interplay between Siderophores and Colibactin Genotoxin Biosynthetic Pathways in Escherichia coli

Author

Eric Oswald, Christian Chalut, Marie Penary, Patricia Martin, Maïwenn Olier, Jean-Philippe Nougayrède, Delphine Payros, Michèle Boury, Marc Audebert, Christophe Garcie, Ingrid Marcq, Sören Schubert, Giuseppe Magistro, Centre de Physiopathologie Toulouse Purpan (CPTP - U1043 INSERM - UMR5282 CNRS - UT3), Université Toulouse III - Paul Sabatier (UT3), 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), Service de Bactériologie-Hygiène [CHU Toulouse] (Hôpital Purpan), Centre Hospitalier Universitaire de Toulouse, Neuro-Gastroentérologie et Nutrition (NGN), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole supérieure d'agriculture de Purpan (ESAP), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), CHU Toulouse [Toulouse], Ecole supérieure d'agriculture de Purpan (ESAP)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Métabolisme et Xénobiotiques (ToxAlim-MeX), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), FEDER (MYCA), Centre de Physiopathologie de Toulouse Purpan (CPTP, Sepsis: the critical role of iron), French National Research Agency (ANR), Institut de Recherche en Santé Digestive (IRSD ), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Chalut, Christian, Service Bactériologie et hygiène [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Institut National de la Recherche Agronomique (INRA)-Ecole supérieure d'agriculture de Purpan (ESAP)

Subjects
Siderophore, GENE-CLUSTER, Siderophores, Transferases (Other Substituted Phosphate Groups), HIGH-PATHOGENICITY ISLAND, COMPLETE GENOME SEQUENCE, PHOSPHOPANTETHEINYL TRANSFERASE, PHYLOGENETIC DISTRIBUTION, 4'-PHOSPHOPANTETHEINYL TRANSFERASE, IRON ACQUISITION, MAMMALIAN-CELLS, IN-VIVO, VIRULENCE, medicine.disease_cause, Yersiniabactin, chemistry.chemical_compound, Mice, Gene cluster, Biology (General), Escherichia coli Infections, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Escherichia coli Proteins, Glycopeptides, Isoenzymes, Female, Research Article, Genomic Islands, QH301-705.5, Immunology, Virulence, Biology, Microbiology, Enterobactin, 03 medical and health sciences, Bacterial Proteins, Phenols, Virology, Sepsis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Escherichia coli, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Gene, 030304 developmental biology, 030306 microbiology, RC581-607, Pathogenicity island, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Mice, Inbred C57BL, Thiazoles, chemistry, Polyketides, Mutation, Parasitology, Immunologic diseases. Allergy, Peptides, Gene Deletion, Mutagens
Abstract

In Escherichia coli, the biosynthetic pathways of several small iron-scavenging molecules known as siderophores (enterobactin, salmochelins and yersiniabactin) and of a genotoxin (colibactin) are known to require a 4′-phosphopantetheinyl transferase (PPTase). Only two PPTases have been clearly identified: EntD and ClbA. The gene coding for EntD is part of the core genome of E. coli, whereas ClbA is encoded on the pks pathogenicity island which codes for colibactin. Interestingly, the pks island is physically associated with the high pathogenicity island (HPI) in a subset of highly virulent E. coli strains. The HPI carries the gene cluster required for yersiniabactin synthesis except for a gene coding its cognate PPTase. Here we investigated a potential interplay between the synthesis pathways leading to the production of siderophores and colibactin, through a functional interchangeability between EntD and ClbA. We demonstrated that ClbA could contribute to siderophores synthesis. Inactivation of both entD and clbA abolished the virulence of extra-intestinal pathogenic E. coli (ExPEC) in a mouse sepsis model, and the presence of either functional EntD or ClbA was required for the survival of ExPEC in vivo. This is the first report demonstrating a connection between multiple phosphopantetheinyl-requiring pathways leading to the biosynthesis of functionally distinct secondary metabolites in a given microorganism. Therefore, we hypothesize that the strict association of the pks island with HPI has been selected in highly virulent E. coli because ClbA is a promiscuous PPTase that can contribute to the synthesis of both the genotoxin and siderophores. The data highlight the complex regulatory interaction of various virulence features with different functions. The identification of key points of these networks is not only essential to the understanding of ExPEC virulence but also an attractive and promising target for the development of anti-virulence therapy strategies., Author Summary The synthesis of numerous molecules involved in the virulence potential and fitness of pathogenic bacteria requires a particular enzyme family, i.e. phosphopantetheinyl transferases (PPTases). To date, the synthesis of a given bioactive metabolite was thought to require a specific PPTase. As PPTases are being investigated as promising targets for antibacterial development, we addressed the question of a possible functional interchangeability between PPTases in Escherichia coli. PPTases are known to be involved in the synthesis of low-molecular weight iron chelators (siderophores), and of a genotoxin named colibactin. Here we demonstrated interplay between the synthesis pathways leading to the production of siderophores and of colibactin. We showed that inactivation of both PPTases abolished the virulence of extra-intestinal pathogenic E. coli (ExPEC) in a mouse sepsis model. To our knowledge, this is the first demonstration of interplay between multiple PPTases-requiring pathways leading to the biosynthesis of functionally distinctive virulence factors, in a given microorganism. The extensive substrate specificity of PPTase ClbA could account for the co-selection and co-evolution of genomic islands encoding colibactin and yersiniabactin siderophore.

Published
2013
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