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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们的实验室研究了革兰氏病原体金黄色葡萄球菌的内在抗菌耐药机制。研究的第一个领域我们的实验室研究是葡萄球菌附件调节剂（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剂。我们已经证明，SARA是对多种结构和机械上独特抗菌剂的固有抗药性的完全表达所必需的。此外，该SARA介导的机制控制抗菌积累。万古霉素中间体金黄色葡萄球菌于1997年出现，对最后一架抗稳定球菌剂万古霉素构成威胁。万古霉素对于治疗由耐甲氧西林链球菌引起的感染尤其重要，金黄色葡萄球菌通常是抗抗生素的多种抗生素。我们已经证明，萨拉在三个无关的签证菌株中灭活增加了万古霉素的易感性，如降低：琼脂扩散最小抑制浓度（MIC）； E-Tes​​t MIC；在万古霉素梯度上生长的距离；检测到的高水平万古霉素菌落。研究的第二个区域是金黄色葡萄球菌诱导的多种抗菌耐药机制。金黄色葡萄球菌用非甾体类抗炎水杨酸盐的生长降低了这种生物对多种在结构和机械学上独特的抗菌剂的敏感性。金黄色葡萄球菌的生长带有水杨酸酯会导致诱导与葡萄糖酸盐和甲酸盐代谢有关的基因，以及抑制糖异生和糖酵解所需的基因。此外，水杨酸酯诱导上调了两个抗生素靶基因，并下调了多药外排泵基因抑制剂（MGRA）和SARR，这抑制了对抗菌耐药性重要的基因（SARA）。我们假设这些水杨酸酯诱导的改变共同代表了一种独特的机制，该机制使金黄色葡萄球菌能够抵抗抗菌应激和毒性。总体而言，这两个研究领域都确定了潜在的细胞靶标，用于开发新型抗史典礼剂。