Dataset Information


Switching on antibiotic resistance in Staphylococcus aureus – Contribution of WalK and VraS histidine kinases in the development of vancomycin and daptomycin resistance

ABSTRACT: Staphylococcus aureus is a notorious bacterial pathogen that causes a broad range of human diseases, and isolates that are resistant to several antibiotic classes including last resort antibiotics like vancomycin and daptomycin complicate the situation. We characterized S. aureus VC40, a strain that shows full resistance to vancomycin (MIC of 64 µg/ml) and daptomycin (MIC of 4 µg/ml) as well as a decreased susceptibility to further cell wall active agents. Genome sequencing revealed mutations in genes encoding the histidine kinases WalK and VraS that control cell envelope related processes and gene expression profiling indicated the induction of the respective regulons in strain VC40. Reconstitution of the mutations in walK or vraS into the susceptible S. aureus NCTC 8325 background resulted in a considerably increased resistance to vancomycin and daptomycin with MICs surpassing the clinical breakpoints for these antibiotics, thereby generating vancomycin-intermediate S. aureus (VISA) strains. As observed for S. aureus VC40, the walKwalk and vraS mutations also led to an increased expression of the respective regulons in the NCTC 8325 background. Phenotypic studies showed that S. aureus VC40 as well as the walKwalk and vraS mutants of strain NCTC 8325 were characterized by a significantly thickened cell wall, a decreased growth rate, a reduced autolytic activity and an increased resistance to lysostaphin-induced lysis. These results demonstrate that the WalK and VraS histidine kinases act as major switches which allow S. aureus to rapidly develop vancomycin resistance up to the VISA level via mutation of one single gene locus and concomitantly contribute to cross-resistance to other antibiotics including the last resort antibiotic daptomycin. Microarray was used to evaluate alteration in the transcriptome of mutS mutant and compared to the parental strain VC40

ORGANISM(S): Staphylococcus aureus subsp. aureus Mu50  

SUBMITTER: Peter Sass   Patrice Francois  FRANCOIS Patrice  Jacques Schrenzel  Anne Berscheid  Axel Strittmatter  Gerhard Gottschalk  Gabriele Bierbaum 

PROVIDER: E-GEOD-46887 | ArrayExpress | 2014-08-18



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Generation of a vancomycin-intermediate Staphylococcus aureus (VISA) strain by two amino acid exchanges in VraS.

Berscheid Anne A   François Patrice P   Strittmatter Axel A   Gottschalk Gerhard G   Schrenzel Jacques J   Sass Peter P   Bierbaum Gabriele G  

The Journal of antimicrobial chemotherapy 20140806 12

OBJECTIVES: Staphylococcus aureus is a notorious bacterial pathogen and antibiotic-resistant isolates complicate current treatment strategies. We characterized S. aureus VC40, a laboratory mutant that shows full resistance to glycopeptides (vancomycin and teicoplanin MICs ≥32 mg/L) and daptomycin (MIC = 4 mg/L), to gain deeper insights into the underlying resistance mechanisms. METHODS: Genomics and transcriptomics were performed to characterize changes that might contribute to development of re  ...[more]

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