STAPHYLOCOCCAL VANCOMYCIN AND METHICILLIN RESISTANCE

描述（改编自申请人的摘要）： 严重的金黄色葡萄球菌疾病，如菌血症和传染性 心内膜炎用有效的抗微生物剂积极治疗。 这些疾病的死亡率分别为80%和100%， 前抗生素时代大多数医院菌株的S。金黄色葡萄球菌现在 耐甲氧西林（MRSA），并且此类菌株通常对甲氧西林耐药。 多种抗生素。糖肽类抗生素万古霉素是唯一 剩余的抗生素S.金黄色葡萄球菌仍然一致敏感。 最近，万古霉素耐药菌株已出现在患者在长期 万古霉素治疗（所谓的糖肽中间体敏感S.金黄色 或GISA菌株）。我们必须了解 万古霉素耐药菌株。万古霉素耐药菌株已被 在研究者实验室中逐步选择。很可能抵抗力量 机制涉及多个突变，是多方面的。调查人员 建议研究S.万古霉素和甲氧西林 实验室和临床菌株的耐药性，他们的工作被组织成 三大调查主线：一，万古霉素的表型研究 电阻; II.万古霉素抗性的基因型研究;和III.应力 基因和蛋白表达在甲氧西林和万古霉素耐药中的作用。在我， 他们将研究肽聚糖磷壁酸的组成和结构， 和脂磷壁酸，并试图了解其机制 在这些菌株中观察到的自溶活性降低。他们将试图 通过研究GISA菌株对NaCl的敏感性， 相容性溶质的积累，以及Na+离子是否积累 在NaCl胁迫下，细胞内的生长抑制水平。第二，他们将 试图发现万古霉素耐药的遗传基础， 转座子诱变研究，直接克隆基因负责 万古霉素耐药，靶基因的克隆和核苷酸序列分析 通过在I中的研究表明在万古霉素耐药性中起作用的基因 以上在III中，他们将研究细胞壁抗生素应激基因的作用， 甲氧西林和万古霉素耐药的蛋白表达 蛋白质组学方法，使用基因芯片技术进行转录谱分析， 选择性捕获转录序列。预计这些研究 将导致用于控制耐甲氧西林的改进方法， 耐万古霉素S.金黄色葡萄球菌感染，并形成发展的基础 新的抗葡萄球菌药物。

DESCRIPTION (Adapted from the Applicant's Abstract): It is imperative that serious Staphylococcus aureus diseases such as bacteremia and infectious endocarditis are treated aggressively with effective antimicrobial agents. These diseases had mortality rates of 80 and 100 percent respectively in the pre-antibiotic era. Most hospital strains of S. aureus are now methicillin-resistant (MRSA), and such strains are typically resistant to multiple other antibiotics. The glycopeptide antibiotic vancomycin was the sole remaining antibiotic to which S. aureus remained uniformly susceptible. Recently, vancomycin-resistant strains have arisen in patients during long-term vancomycin therapy (so called glycopeptide-intermediate susceptible S. aureus or GISA strains). It is imperative that we understand the mechanism of vancomycin resistance in such strains. Vancomycin-resistant strains have been step-selected in the investigators laboratory. It is likely that the resistance mechanism involves several mutations and is multifaceted. The investigators propose to study the mechanisms of S. aureus vancomycin and methicillin resistance in laboratory and clinical strains, and their work is organized into three major lines of investigation: I. Phenotypic studies of vancomycin resistance; II. Genotypic studies of vancomycin resistance; and III. Stress gene and protein expression in methicillin and vancomycin resistance. In I, they will study the composition and structure of peptidoglycan, teichoic acid and lipoteichoic acid in GISA strains, and attempt to understand the mechanism of decreased autolytic activity observed in such strains. They will attempt to understand the increased NaCl-sensitivity of GISA strains through studying the accumulation of compatible solutes, and whether Na+ ions accumulate intracellularly to growth inhibitory levels upon NaCl stress. In II, they will attempt to discover the genetic basis of vancomycin resistance through transposon mutagenesis studies, direct cloning of genes responsible for vancomycin resistance, and cloning and nucleotide sequence analysis of target genes as indicated to play a role in vancomycin resistance through studies in I above. In III, they will study the role of cell wall antibiotic stress gene and protein expression in methicillin and vancomycin resistance through a proteomics approach, transcription profiling using gene chip technology, and by selective capture of transcribed sequences. It is expected that these studies will lead to improved methods for the control of methicillin-resistant and vancomycin-resistance S. aureus infections, and form the basis for development of novel antistaphylococcal agents.