ArticleAntimicrobial agents and chemotherapy2011
Site-specific mutation of Staphylococcus aureus VraS reveals a crucial role for the VraR-VraS sensor in the emergence of glycopeptide resistance.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 42 citations in OpenAlex.
- Staphylococcus aureus sensor histidine kinase VraS mutations linked to antibiotic resistance affect enzymatic catalysis, stability, and substrate interactions.Archives of biochemistry and biophysics · 2026Article
- Evolution under vancomycin selection drives divergent collateral sensitivity patterns inProceedings of the National Academy of Sciences of the United States of America · 2025Article
- A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus.Bioorganic & medicinal chemistry letters · 2025Article
- Combatting Antibiotic-ResistantJournal of chemical information and modeling · 2024Article
- Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms.Journal of translational medicine · 2024Article
- High prevalence of heteroresistance in Staphylococcus aureus is caused by a multitude of mutations in core genes.PLoS biology · 2024Article
- Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms.Research square · 2023Article
- NH125 Sensitizes Staphylococcus aureus to Cell Wall-Targeting Antibiotics through the Inhibition of the VraS Sensor Histidine Kinase.Microbiology spectrum · 2023Article
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- Revisiting the Role of VraTSR inJournal of bacteriology · 2022Article
- The Role of ArlRS and VraSR in Regulating Ceftaroline Hypersusceptibility in Methicillin-ResistantAntibiotics (Basel, Switzerland) · 2021Article
- Long-Term Intrahost Evolution ofFrontiers in microbiology · 2021Article
- Article
- Thermosensitive PBP2a requires extracellular folding factors PrsA and HtrA1 forCommunications biology · 2019Article
- Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases.Journal of medicinal chemistry · 2017Article
- Different Vancomycin-Intermediate Staphylococcus aureus Phenotypes Selected from the Same ST100-hVISA Parental Strain.Microbial drug resistance (Larchmont, N.Y.) · 2017Article
- Article
- A putative cro-like repressor contributes to arylomycin resistance in Staphylococcus aureus.Antimicrobial agents and chemotherapy · 2015Article
- The msaABCR operon regulates resistance in vancomycin-intermediate Staphylococcus aureus strains.Antimicrobial agents and chemotherapy · 2014Article
- Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
An initial response of Staphylococcus aureus to encounter with cell wall-active antibiotics occurs by transmembrane signaling systems that orchestrate changes in gene expression to promote survival. Histidine kinase two-component sensor-response regulators such as VraRS contribute to this response. In this study, we examined VraS membrane sensor phosphotransfer signal transduction and explored the genetic consequences of disrupting signaling by engineering a site-specific vraS chromosomal mutation. We have used in vitro autophosphorylation assay with purified VraS[64-347] lacking its transmembrane anchor region and tested site-specific kinase domain histidine mutants. We identified VraS H156 as the probable site of autophosphorylation and show phosphotransfer in vitro using purified VraR. Genetic studies show that the vraS(H156A) mutation in three strain backgrounds (ISP794, Newman, and COL) fails to generate detectable first-step reduced susceptibility teicoplanin mutants and severely reduces first-step vancomycin mutants. The emergence of low-level glycopeptide resistance in strain ISP794, derived from strain 8325 (ΔrsbU), did not require a functional σ(B), but rsbU restoration could enhance the emergence frequency supporting a role for this alternative sigma factor in promoting glycopeptide resistance. Transcriptional analysis of vraS(H156A) strains revealed a pronounced reduction but not complete abrogation of the vraRS operon after exposure to cell wall-active antibiotics, suggesting that additional factors independent of VraS-driven phosphotransfer, or σ(B), exist for this promoter. Collectively, our results reveal important details of the VraRS signaling system and predict that pharmacologic blockade of the VraS sensor kinase will have profound effects on blocking emergence of cell wall-active antibiotic resistance in S. aureus.
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