VraR Binding to the Promoter Region of Inhibits Its Function in Vancomycin-Intermediate Staphylococcus aureus (VISA) and Heterogeneous VISA.

Acquisition of vancomycin resistance in is often accompanied by a reduction in virulence, but the mechanisms underlying this change remain unclear. The present study was undertaken to investigate this process in a clinical heterogeneous vancomycin-intermediate (hVISA) strain, 10827; an hVISA reference strain, Mu3; and a VISA reference strain, Mu50, along with their respective series of vancomycin-induced resistant strains. In these strains, increasing MICs of vancomycin were associated with increased expression of the vancomycin resistance-associated regulator gene () and decreased expression of virulence genes (, , and ) and virulence-regulated genes (RNAIII, , and ). These results suggested that VraR might have a direct or indirect effect on virulence in In electrophoretic mobility shift assays, VraR did not bind to promoter sequences of , , and genes, but it did bind to the promoter region. In DNase I footprinting assays, VraR protected a 15-nucleotide (nt) sequence in the intergenic region between the P2 and P3 promoters. These results indicated that when is subject to induction by vancomycin, expression of is upregulated, and VraR binding inhibits the function of the Agr quorum-sensing system, causing reductions in the virulence of VISA/hVISA strains. Our results suggested that VraR in is involved not only in the regulation of vancomycin resistance but also in the regulation of virulence.