REGULATION OF MULTIDRUG RESISTANCE IN S AUREUS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our laboratory investigates the intrinsic antimicrobial resistance mechanisms of the Gram-positive pathogen Staphylococcus aureus. The first area of research our laboratory investigates is the involvement of the staphylococcal accessory regulator (sarA) with intrinsic and clinically relevant antibiotic resistance mechanisms. The sarA locus was initially described as a virulence gene regulator. We have demonstrated that sarA is required for the full expression of intrinsic resistance to multiple structurally and mechanistically unique antimicrobials. In addition, this sarA-mediated mechanism controls antimicrobial accumulation. Vancomycin-intermediate S. aureus appeared in 1997 and are a threat to the last stand anti-staphylococcal agent vancomycin. Vancomycin is particularly important for the treatment of infections caused by methicillin-resistant S. aureus, which in general are multiply antibiotic-resistant. We have demonstrated that sarA inactivation in three unrelated sets of VISA strains increased vancomycin susceptibility as revealed by decreased: agar diffusion minimum inhibitory concentrations (MIC); E-test MICs; distances grown on vancomycin gradients; and high-level vancomycin-resistant colonies detected. The second area investigated is the salicylate-induced multiple antimicrobial resistance mechanism of Staphylococcus aureus. Growth of S. aureus with the nonsteroidal anti-inflammatory salicylate reduces susceptibility of this organism to multiple antimicrobials that are structurally and mechanistically unique. Growth of S. aureus with salicylate leads to the induction of genes involved with gluconate and formate metabolism and repression of genes required for gluconeogenesis and glycolysis. In addition, salicylate induction upregulates two antibiotic target genes and downregulates a multidrug efflux pump gene repressor (mgrA) and sarR, which represses a gene (sarA) important for antimicrobial resistance. We hypothesize that these salicylate-induced alterations jointly represent a unique mechanism that allows S. aureus to resist antimicrobial stress and toxicity. Collectively both areas of research have identified potential cellular targets for the development of novel anti-staphylococcal agents.