REGULATION OF MULTIDRUG RESISTANCE IN S AUREUS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们实验室研究了革兰氏阳性病原菌金黄色葡萄球菌的内在耐药机制。我们实验室调查的第一个研究领域是葡萄球菌辅助调节因子(SARA)与内在和临床相关的抗生素耐药机制的参与。SarA基因座最初被描述为毒力基因调节因子。我们已经证明，SARA是充分表达对多种结构和机械上独特的抗菌药的内在耐药性所必需的。此外，这种SARA介导的机制控制着抗菌素的积累。万古霉素中间体金黄色葡萄球菌出现于1997年，是对万古霉素的最后一种威胁。万古霉素对于治疗由耐甲氧西林金黄色葡萄球菌引起的感染特别重要，这种金黄色葡萄球菌通常具有多重抗药性。我们已经证明，在三组不相关的VISA菌株中，SARA失活增加了万古霉素敏感性，其结果显示：琼脂扩散最低抑菌浓度(MIC)、E-TEST MIC、在万古霉素梯度上生长的距离和检测到的高水平万古霉素耐药菌落。第二个研究领域是水杨酸诱导金黄色葡萄球菌多重耐药的机制。金黄色葡萄球菌的生长与非类固醇抗炎水杨酸盐降低了该微生物对多种抗菌剂的敏感性，这些抗菌剂在结构和机械上都是独特的。金黄色葡萄球菌在水杨酸盐作用下生长，可诱导葡萄糖酸和甲酸代谢相关基因的表达，并抑制糖异生和糖酵解所需基因的表达。此外，水杨酸诱导上调了两个抗生素靶基因，下调了多药外排泵基因抑制子(MGRA)和SarR，后者抑制了一个重要的抗菌素耐药性基因(SarA)。我们推测，这些水杨酸盐诱导的改变共同代表了一种独特的机制，使金黄色葡萄球菌能够抵抗抗菌素压力和毒性。总的来说，这两个研究领域都确定了开发新型抗葡萄球菌药物的潜在细胞靶点。

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.