Anjou Cyril, Royer Marie, Bertrand Émilie, Bredon Marius, Le Bris Julie, Salgueiro Iria Alonso, Caulat Léo C, Dupuy Bruno, Barbut Frédéric, Morvan Claire, Rolhion Nathalie, Martin-Verstraete Isabelle
Institut Pasteur, Université Paris Cité, UMR CNRS 6047, Laboratoire Pathogenèse des Bactéries Anaérobies, F-75015, Paris, France.
Institut Pasteur, Université Paris Cité, UMR CNRS 6047, Unité Écologie et Évolution de la Résistance aux Antibiotiques, Paris, France.
NPJ Biofilms Microbiomes. 2024 Sep 17;10(1):86. doi: 10.1038/s41522-024-00551-3.
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 and strongly affect physiology. Finally, we showed that AF has less impact on human gut microbiota than vancomycin.
金诺芬（AF）曾用于治疗类风湿性多关节炎，如今其作为抗菌剂的用途重新引起了人们的关注。AF是硫氧还蛋白还原酶（TrxB）的抑制剂，TrxB是一种参与硫醇和蛋白质修复的酶，AF对包括艰难梭菌在内的多种细菌具有抗菌活性，艰难梭菌是一种导致抗生素相关性腹泻的肠道病原体。多项研究证明了AF对艰难梭菌生理机能的影响，但耐药机制以及对微生物群影响的关键问题仍未得到解决。我们通过研究TrxB多样性的影响以及产生和表征适应性突变来探索潜在的耐药机制。我们发现，虽然trxB基因失活的突变体对AF的最低抑菌浓度（MIC）较低，但临床菌株中天然存在的TrxB数量并不影响MIC。长期暴露于AF后分离出的所有稳定突变均存在于σ因子的抗σ因子中，并对生理机能有强烈影响。最后，我们证明AF对人类肠道微生物群的影响小于万古霉素。
