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- Title
Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits.
- Authors
Buddle, Jessica E.; Thompson, Lucy M.; Williams, Anne S.; Wright, Rosanna C. T.; Durham, William M.; Turner, Claire E.; Chaudhuri, Roy R.; Brockhurst, Michael A.; Fagan, Robert P.
- Abstract
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 resistance has yet to be reported for C. difficile, although it is not known if this is due to constraints upon resistance evolution in this species. Here, we show that resistance to vancomycin can evolve rapidly under ramping selection but is accompanied by fitness costs and pleiotropic trade-offs, including sporulation defects that would be expected to severely impact transmission. We identified 2 distinct pathways to resistance, both of which are predicted to result in changes to the muropeptide terminal D-Ala-D-Ala that is the primary target of vancomycin. One of these pathways involves a previously uncharacterised D,D-carboxypeptidase, expression of which is controlled by a dedicated two-component signal transduction system. Our findings suggest that while C. difficile is capable of evolving high-level vancomycin resistance, this outcome may be limited clinically due to pleiotropic effects on key pathogenicity traits. Moreover, our data identify potential mutational routes to resistance that should be considered in genomic surveillance. Clostridioides difficile is a human pathogen primarily treated with the antibiotic vancomycin. High-level vancomycin resistance is a serious problem in other pathogens, not yet for C. difficile. This study identifies two resistance pathways in C. difficile, which evolve rapidly but with fitness costs that could affect transmission.
- Subjects
VANCOMYCIN resistance; CLOSTRIDIOIDES difficile; GLYCOPEPTIDE antibiotics; CELLULAR signal transduction; VANCOMYCIN
- Publication
PLoS Biology, 2024, Vol 22, Issue 8, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002741