In the Literature

The S. aureus “vancomycin-intermediate S. aureus (VISA) phenotype” (i.e., a thickened cell wall in association with diminished autolytic activity, together with an increase in the MIC of vancomycin into the range of intermediate susceptibility) can be reproduced by in vitro exposure to vancomycin. A similar effect has been observed in some patients during vancomycin therapy. Mwangi and colleagues at Rockefeller University (New York City) followed the genetic evolution of a strain of methicillin-resistant S. aureus (MRSA) that was repeatedly recovered from the bloodstream of a patient for whom vancomycin treatment failed. The authors performed whole-genome sequencing in an attempt to identify mutations associated with the emergence of this phenotype with reduced susceptibility to vancomycin. Reduced susceptibility to imipenem and rifampin and associated mutations were also observed after administration of these antibiotics to the patient. Susceptibility to vancomycin gradually decreased in discrete steps, with an initial MIC of 1 mg/mL eventually reaching an MIC of 8 mg/mL. This was associated with an increase in the MIC of daptomycin—an effect that has previously been reported. The increase in the MIC of vancomycin was accompanied by a sequential series of mutations and the appearance of 18 distinct mutations, with an MIC of 8 mg/mL having been reached after 2.5 months of therapy. One of the early mutations observed, which was associated with an increase in the MIC to 4 mg/mL, was in vraR, which encodes a response regulator of a 2-component system. The next increase in the MIC (to 6 mg/mL) was associated with a mutation in SA1249, a gene of unknown function. An additional increase in the MIC (to 8 mg/mL) was associated with mutations in yycH and agrC; the former is within a gene cluster associated with a response regulator of a 2-component system. Alterations of the agr locus, which encodes a quorum-sensing regulator controlling a number of virulence and cell surface genes, has previously been associated with reduced susceptibility to vancomycin. The potential importance of the vraR mutation is highlighted by its early occurrence and by the separate observation that mutations in the vraR operon were also identified in 6 VISA isolates from a variety of geographic locations. VraS/VraR is a 2-component regulatory system of S. aureus that senses and is induced by cell wall–active antibiotics, including vancomycin, and that transcriptionally controls induction of a number of cell wall genes, including those encoding pbp2. It is required along with other factors, including mecA, for expression of resistance to oxacillin [1]. Deletion of vraR lowers the MIC for S. aureus to oxacillin and also vancomycin, and its upregulation was associated with an increased MIC in the single strain examined. Thus, it can be speculated that the mutation in this gene identified by Mwangi and colleagues affects the regulation of gene expression. Whatever the mechanism proves to be, the data summarized here suggest that mutations in the vraR operon are strongly associated with the reduced susceptibility to vancomycin and the emergence of the VISA phenotype.