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Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits.
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.
Affiliation
  • Buddle JE; Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom.
  • Thompson LM; Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom.
  • Williams AS; Department of Physics and Astronomy, University of Sheffield, Sheffield, United Kingdom.
  • Wright RCT; Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom.
  • Durham WM; Department of Physics and Astronomy, University of Sheffield, Sheffield, United Kingdom.
  • Turner CE; Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom.
  • Chaudhuri RR; Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom.
  • Brockhurst MA; Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom.
  • Fagan RP; Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom.
PLoS Biol ; 22(8): e3002741, 2024 Aug.
Article in En | MEDLINE | ID: mdl-39146240
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Vancomycin / Clostridioides difficile / Vancomycin Resistance / Anti-Bacterial Agents Limits: Humans Language: En Journal: PLoS Biol Journal subject: BIOLOGIA Year: 2024 Document type: Article Affiliation country: United kingdom Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Vancomycin / Clostridioides difficile / Vancomycin Resistance / Anti-Bacterial Agents Limits: Humans Language: En Journal: PLoS Biol Journal subject: BIOLOGIA Year: 2024 Document type: Article Affiliation country: United kingdom Country of publication: United States