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

IF 7.8 1区生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

npj Biofilms and Microbiomes Pub Date : 2024-09-17 DOI:10.1038/s41522-024-00551-3

Cyril Anjou, Marie Royer, Émilie Bertrand, Marius Bredon, Julie Le Bris, Iria Alonso Salgueiro, Léo C. Caulat, Bruno Dupuy, Frédéric Barbut, Claire Morvan, Nathalie Rolhion, Isabelle Martin-Verstraete

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Abstract

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^B and strongly affect physiology. Finally, we showed that AF has less impact on human gut microbiota than vancomycin.

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艰难梭菌对呋喃丹的适应机制及其对人体肠道微生物群的影响

奥拉诺芬（Auranofin，AF）曾是一种治疗类风湿性多关节炎的药物，因其可用作抗菌剂而再次受到关注。AF 是硫氧还原酶（TrxB）的抑制剂，TrxB 是一种硫醇和蛋白质修复酶，对包括艰难梭菌在内的多种细菌具有抗菌活性，艰难梭菌是一种肠道病原体，会引起抗生素后腹泻。一些研究表明了 AF 对艰难梭菌生理机能的影响，但抗药性机制和对微生物群的影响等关键问题仍未得到解决。我们通过研究 TrxB 多样性的影响以及适应性突变的产生和特征，探索了潜在的抗性机制。我们发现，如果 trxB 基因失活的突变体对甲胺磷的 MIC 较低，那么临床菌株中天然存在的 TrxB 数量并不会影响 MIC。长期接触甲胎蛋白后分离到的所有稳定突变都发生在σB的抗σ因子中，并对生理产生强烈影响。最后，我们还发现，与万古霉素相比，甲胎蛋白对人体肠道微生物群的影响较小。

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来源期刊

npj Biofilms and Microbiomes Immunology and Microbiology-Microbiology

CiteScore

12.10

自引率

3.30%

发文量

审稿时长

9 weeks

期刊介绍： npj Biofilms and Microbiomes is a comprehensive platform that promotes research on biofilms and microbiomes across various scientific disciplines. The journal facilitates cross-disciplinary discussions to enhance our understanding of the biology, ecology, and communal functions of biofilms, populations, and communities. It also focuses on applications in the medical, environmental, and engineering domains. The scope of the journal encompasses all aspects of the field, ranging from cell-cell communication and single cell interactions to the microbiomes of humans, animals, plants, and natural and built environments. The journal also welcomes research on the virome, phageome, mycome, and fungome. It publishes both applied science and theoretical work. As an open access and interdisciplinary journal, its primary goal is to publish significant scientific advancements in microbial biofilms and microbiomes. The journal enables discussions that span multiple disciplines and contributes to our understanding of the social behavior of microbial biofilm populations and communities, and their impact on life, human health, and the environment.