ArticleAntimicrobial agents and chemotherapy2013
Decreased vancomycin susceptibility in Staphylococcus aureus caused by IS256 tempering of WalKR expression.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 65 citations in OpenAlex.
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- Comparative Genomics Identifies Novel Genetic Changes Associated with Oxacillin, Vancomycin and Daptomycin Susceptibility in ST100 Methicillin-ResistantAntibiotics (Basel, Switzerland) · 2023Article
- The WalRK Two-Component System Is Essential for Proper Cell Envelope Biogenesis in Clostridioides difficile.Journal of bacteriology · 2022Article
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- Antibiotic resistance alters through iron-regulating Sigma factors during the interaction of Staphylococcus aureus and Pseudomonas aeruginosa.Scientific reports · 2021Article
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- Vancomycin resistantJournal of advanced research · 2020Review
- Evolution of Multi-Resistance to Vancomycin, Daptomycin, and Linezolid in Methicillin-ResistantFrontiers in microbiology · 2020Article
- Using genomics to understand meticillin- and vancomycin-resistantMicrobial genomics · 2020Review
- Genome-Based Prediction of Bacterial Antibiotic Resistance.Journal of clinical microbiology · 2019Review
- ISFrontiers in microbiology · 2019Article
- Staphylococcal Plasmids, Transposable and Integrative Elements.Microbiology spectrum · 2018Review
- Genomic exploration of sequential clinical isolates reveals a distinctive molecular signature of persistent Staphylococcus aureus bacteraemia.Genome medicine · 2018Article
- Reconstruction of the Vancomycin-SusceptibleFrontiers in microbiology · 2018Article
- Bacterial genome sequencing in clinical microbiology: a pathogen-oriented review.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2017Review
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Vancomycin-intermediate Staphylococcus aureus (VISA) strains often arise by mutations in the essential two-component regulator walKR; however their impact on walKR function has not been definitively established. Here, we investigated 10 MRSA strains recovered serially after exposure of vancomycin-susceptible S. aureus (VSSA) JKD6009 to simulated human vancomycin dosing regimens (500 mg to 4,000 mg every 12 h) using a 10-day hollow fiber infection model. After continued exposure to the vancomycin regimens, two isolates displayed reduced susceptibility to both vancomycin and daptomycin, developing independent IS256 insertions in the walKR 5' untranslated region (5' UTR). Quantitative reverse transcription-PCR (RT-PCR) revealed a 50% reduction in walKR gene expression in the IS256 mutants compared to the VSSA parent. Green fluorescent protein (GFP) reporter analysis, promoter mapping, and site-directed mutagenesis confirmed these findings and showed that the IS256 insertions had replaced two SigA-like walKR promoters with weaker, hybrid promoters. Removal of IS256 reverted the phenotype to VSSA, showing that reduced expression of WalKR did induce the VISA phenotype. Analysis of selected WalKR-regulated autolysins revealed upregulation of ssaA but no change in expression of sak and sceD in both IS256 mutants. Whole-genome sequencing of the two mutants revealed an additional IS256 insertion within agrC for one mutant, and we confirmed that this mutation abolished agr function. These data provide the first substantial analysis of walKR promoter function and show that prolonged vancomycin exposure can result in VISA through an IS256-mediated reduction in walKR expression; however, the mechanisms by which this occurs remain to be determined.
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