REGULATION OF MULTIDRUG RESISTANCE IN S AUREUS

金黄色葡萄球菌多重耐药性的调控

• 批准号: 7610362
• 负责人: JOHN E GUSTAFSON
• 金额: $ 5.23万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610362
• 关键词: Agar; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Area; Computer Retrieval of Information on Scientific Projects Database; Development; Diffusion; Formates; Funding; Gene Targeting; Genes; Glycolysis/Gluconeogenesis Pathway; Grant; Growth; Infection; Institution; Laboratories; Mediating; Metabolism; Minimum Inhibitory Concentration measurement; Multi-Drug Resistance; Organism; Predisposition; Regulation; Regulator Genes; Research; Research Personnel; Resistance; Resources; Source; Staphylococcus aureus; Stress; Testing; Toxic effect; United States National Institutes of Health; Vancomycin; Vancomycin Resistance; Virulence; antimicrobial; cellular targeting; clinically relevant; efflux pump; gene induction; gene repression; gluconate; methicillin resistant Staphylococcus aureus; novel; pathogen; resistance mechanism; salicylate

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 我们的实验室研究革兰氏阳性病原体金黄色葡萄球菌的内在抗菌机制。我们实验室研究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关系。 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制独特的抗菌药物的内在耐药性所必需的。此外，这种 sarA 介导的机制控制抗菌药物的积累。万古霉素中间体金黄色葡萄球菌于 1997 年出现，对最后的抗葡萄球菌药物万古霉素构成威胁。万古霉素对于治疗耐甲氧西林金黄色葡萄球菌引起的感染特别重要，这些感染通常具有多种抗生素耐药性。我们已经证明，三组不相关的 VISA 菌株中 sarA 失活会增加万古霉素敏感性，具体表现为： 琼脂扩散最小抑制浓度 (MIC)；电子测试 MIC；万古霉素梯度上生长的距离；并检测到高水平的万古霉素耐药菌落。研究的第二个领域是水杨酸盐诱导的金黄色葡萄球菌多重耐药机制。金黄色葡萄球菌与非甾体抗炎水杨酸盐的生长降低了该生物体对结构和机制独特的多种抗菌剂的敏感性。金黄色葡萄球菌与水杨酸盐的生长导致与葡萄糖酸和甲酸盐代谢相关的基因的诱导以及糖异生和糖酵解所需的基因的抑制。此外，水杨酸盐诱导上调两个抗生素靶基因并下调多药外排泵基因阻遏物（mgrA）和sarR，后者抑制对抗菌素耐药性重要的基因（sarA）。我们假设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应激和毒性。两个研究领域共同确定了开发新型抗葡萄球菌药物的潜在细胞靶标。