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Adaptation mechanisms of Clostridioides difficile to auranofin and its impact on human gut microbiota

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  • معلومة اضافية
    • Contributors:
      Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)); Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); Centre de Recherche Saint-Antoine (CRSA); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU); FHU Paris Center for Microbiome Medicine (FHU PaCeMM); Génomique évolutive des Microbes / Microbial Evolutionary Genomics; Ecole Doctorale Complexité du Vivant (ED515); Sorbonne Université (SU); Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); CHU Saint-Antoine AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Institut universitaire de France (IUF); Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.); This work was supported by the Fondation pour la Recherche Médicale (grant numbers ECO202006011710 and FDT202304016494) and by the Institut Pasteur for the funding of the PhD contract of C.A. and by the Institut Universitaire de France for I.M.-V.
    • بيانات النشر:
      CCSD
      Springer Nature published in partnership with Nanyang Technological University
    • الموضوع:
      2024
    • Collection:
      Institut Pasteur: HAL
    • نبذة مختصرة :
      International audience ; Auranofin (AF), a former rheumatoid polyarthritis treatment, gained renewed interest for its use as an antimicrobial. AF is an inhibitor of thioredoxin reductase (TrxB), a thiol and protein repair enzyme, with an antibacterial activity against several bacteria including C. difficile, an enteropathogen causing post-antibiotic diarrhea. Several studies demonstrated the effect of AF on C. difficile physiology, but the crucial questions of resistance mechanisms and impact on microbiota remain unaddressed. We explored potential resistance mechanisms by studying the impact of TrxB multiplicity and by generating and characterizing adaptive mutations. We showed that if mutants inactivated for trxB genes have a lower MIC of AF, the number of TrxBs naturally present in clinical strains does not impact the MIC. All stable mutations isolated after AF long-term exposure were in the anti-sigma factor of σB and strongly affect physiology. Finally, we showed that AF has less impact on human gut microbiota than vancomycin.
    • Relation:
      info:eu-repo/semantics/altIdentifier/pmid/39284817; PUBMED: 39284817; PUBMEDCENTRAL: PMC11405772
    • الرقم المعرف:
      10.1038/s41522-024-00551-3
    • الدخول الالكتروني :
      https://hal.science/hal-04756892
      https://hal.science/hal-04756892v1/document
      https://hal.science/hal-04756892v1/file/s41522-024-00551-3.pdf
      https://doi.org/10.1038/s41522-024-00551-3
    • Rights:
      http://creativecommons.org/licenses/by-nc-nd/ ; info:eu-repo/semantics/OpenAccess
    • الرقم المعرف:
      edsbas.2F35B266