Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits

• DOI: 10.1371/journal.pbio.3002741
• Publication Date: 2024-08-15T17:22:05Z
• Authors: Jessica E. Buddle; Lucy M. Thompson; Anne S. Williams; Rosanna C. T. Wright; William M. Durham; Claire E. Turner; Roy R. Chaudhuri; Michael A. Brockh...; Robert P. Fagan
• Keywords: Spores, Bacterial; QH301-705.5; Clostridioides difficile; Vancomycin Resistance; Gene Expression Regulation, Bacterial; Anti-Bacterial Agents; Bacterial Proteins; Vancomycin; Mutation; Humans; Genetic Fitness; Biology (General); Research Article; Signal Transduction

Clostridioides difficile is an important human pathogen, for which there are very limited treatment options, primarily the glycopeptide antibiotic vancomycin. In recent years, vancomycin resistance has emerged as a serious problem in several gram-positive pathogens, but high-level yet to be reported C . , although it not known if this due constraints upon evolution species. Here, we show that can evolve rapidly under ramping selection accompanied by fitness costs and pleiotropic trade-offs, including sporulation defects would expected severely impact transmission. We identified 2 distinct pathways resistance, both of predicted result changes muropeptide terminal D-Ala-D-Ala primary target One these involves previously uncharacterised D,D-carboxypeptidase, expression controlled dedicated two-component signal transduction system. Our findings suggest while capable evolving outcome may clinically effects on key pathogenicity traits. Moreover, our data identify potential mutational routes should considered genomic surveillance.