Adaptation mechanisms of Clostridioides difficile to auranofin and its impact on human gut microbiota
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 σ<sup>B</sup> and strongly affect physiology. Finally, we showed that AF has less impact on human gut microbiota than vancomycin.
Authors
- Julie Le Bris (ORCID: https://orcid.org/0009-0003-5500-0657)
- Cyril Anjou (ORCID: https://orcid.org/0000-0002-3951-1495)
- Claire Morvan (ORCID: https://orcid.org/0000-0001-8435-0523)
- Isabelle Martin‐Verstraete (ORCID: https://orcid.org/0000-0002-8376-7690)
- Marius Bredon (ORCID: https://orcid.org/0000-0001-7396-8870)
- Iria Alonso Salgueiro
- Léo C. Caulat (ORCID: https://orcid.org/0000-0002-5940-2990)
- Nathalie Rolhion (ORCID: https://orcid.org/0000-0002-2946-4808)
- Bruno Dupuy (ORCID: https://orcid.org/0000-0001-7176-8453)
- Émilie Bertrand
- Marie Royer
- Frédéric Barbut (ORCID: https://orcid.org/0000-0002-4165-0670)
Institutions
- Délégation Paris 5 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Sorbonne Nouvelle (FR)
- Institut Universitaire de France (FR)
- Université Paris Cité (FR)
- Sorbonne Université (FR)
- Sorbonne Paris Cité (FR)
- Hôpital Saint-Antoine (FR)
- Fédération Hospitalo-Universitaire, Paris Center for Microbiome Medicine (FR)
- Evolutionary Genomics (United States) (US)
- CNR de la Résistance aux Antibiotiques (FR)
- Centre de Recherche Saint-Antoine (FR)
Publication Details
- Journal
- npj Biofilms and Microbiomes
- Published
- 2024-09-17
- DOI
- https://doi.org/10.1038/s41522-024-00551-3
- Citations
- 2
- Primary Topic
- Clostridium difficile and Clostridium perfringens research
- Type
- article
- Field-Weighted Citation Impact
- 0.78
Funders
- Fondation pour la Recherche Médicale
- Institut Pasteur
- Institut Universitaire de France