ArticleThe Journal of antimicrobial chemotherapy2020
Constitutive expression of the cryptic vanGCd operon promotes vancomycin resistance in Clostridioides difficile clinical isolates.
Article in The Journal of antimicrobial chemotherapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Omadacycline andThe Annals of pharmacotherapy · 2023Pooled it
- Fecal Pharmacokinetics and Gut Microbiome Effects of Oral Omadacycline Versus Vancomycin in Healthy Volunteers.The Journal of infectious diseases · 2024Trial
- Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2022Trial
- Genomic evolution and re-emergence of a multidrug-resistantEmerging microbes & infections · 2026Article
- Article
- Clostridioides difficile pathogenesis and control.Nature reviews. Microbiology · 2026Review
- A severe Clostridioides difficile ribotype 027 infection in Beijing, China, july 2024.BMC infectious diseases · 2025Article
- Differences in virulence and drug resistance betweenVirulence · 2025Article
- Review
- Increase ofMicrobiology spectrum · 2025Article
- Minimum Inhibitory Concentration Increase inMicroorganisms · 2025Article
- Community-AcquiredInternational journal of molecular sciences · 2025Review
- Identification of a family of peptidoglycan transpeptidases reveals thatProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits.PLoS biology · 2024Article
- Reduced Vancomycin Susceptibility in Clostridioides difficile Is Associated With Lower Rates of Initial Cure and Sustained Clinical Response.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2024Article
- Review
- Genetic determinants of resistance to antimicrobial therapeutics are rare in publicly available Clostridioides difficile genome sequences.The Journal of antimicrobial chemotherapy · 2024Article
- Histidine kinase-mediated cross-regulation of the vancomycin-resistance operon in Clostridioides difficile.Molecular microbiology · 2024Article
- Comparison of fidaxomicin, metronidazole and vancomycin for initial episode and recurrence ofHeliyon · 2024Article
- Article
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
objectivesTo describe, for the first time (to the best of our knowledge), the genetic mechanisms of vancomycin resistance in clinical isolates of Clostridioides difficile ribotype 027.
methodsClinical isolates and laboratory mutants were analysed: genomically to identify resistance mutations; by transcriptional analysis of vanGCd, the vancomycin resistance operon encoding lipid II d-alanine-d-serine that is less bound by vancomycin than native lipid II d-alanine-d-alanine; by imaging of vancomycin binding to cell walls; and for changes in vancomycin bactericidal activity and autolysis.
resultsVancomycin-resistant laboratory mutants and clinical isolates acquired mutations to the vanSR two-component system that regulates vanGCd. The substitutions impaired VanSR's function, resulting in constitutive transcription of vanGCd. Resistance was reversed by silencing vanG, encoding d-alanine-d-serine ligase in the vanGCd operon. In resistant cells, vancomycin was less bound to the cell wall septum, the site where vancomycin interacts with lipid II. Vancomycin's bactericidal activity was reduced against clinical isolates and laboratory mutants (64 and ≥1024 mg/L, respectively) compared with WT strains (4 mg/L). Truncation of the potassium transporter TrkA occurred in laboratory mutants, which were refractory to autolysis, accounting for their survival in high drug concentrations.
conclusionsRibotype 027 evolved first-step resistance to vancomycin by constitutively expressing vanGCd, which is otherwise silent. Experimental evolutions and bactericidal assays show that ribotype 027 can acquire mutations to drastically enhance its tolerance to vancomycin. Thus, further epidemiological studies are warranted to examine the extent to which vancomycin resistance impacts clinical outcomes and the potential for these strains to evolve higher-level resistance, which would be devastating.
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