Physiology of S aureus Vancomycin Resistance

描述(由申请人提供)：当务之急是 金黄色葡萄球菌菌血症和感染性心内膜炎等疾病 使用有效的抗菌剂进行积极治疗。这些疾病 抗生素前的死亡率分别为80%和100% 时代。大多数医院的金黄色葡萄球菌现在对甲氧西林耐药(MRSA)， 这些菌株通常对多种其他抗生素具有抗药性。这个 糖肽抗生素万古霉素是唯一残留的抗生素 金黄色葡萄球菌仍然一致易受感染。最近。万古霉素耐药 在长期使用万古霉素(即所谓的万古霉素)治疗期间，患者会出现菌株 糖肽--中间敏感的金黄色葡萄球菌或GISA菌株)。它是 我们迫切需要了解万古霉素耐药的机制 菌株。本实验室对万古霉素耐药菌株进行了分步筛选。 这种耐药机制很可能涉及几个突变， 多面性。我建议研究金黄色葡萄球菌万古霉素的作用机制 实验室和临床菌株的耐药性。我会研究一下作文，然后 GISA中肽多糖、磷壁酸和脂磷壁酸的结构 菌株，并试图了解自溶能力下降的机制 在这些菌株中观察到的活性。细胞壁的改变似乎与此有关。 在万古霉素耐药方面。我会试着理解增加的 GISA菌株对NaCl的敏感性研究 相容的溶质。以及Na+离子是否在细胞内积累以促进生长 对盐胁迫的抑制水平。有限的研究对理解 将对万古霉素的遗传学基础进行研究。新城疫病毒的核苷酸序列分析 克隆生理学研究表明可能发生改变的选定基因 将进行GISA菌株检测。预计这些研究将导致 改进控制甲氧西林耐药性的方法和 万古霉素耐药金黄色葡萄球菌感染，并形成发展的基础 一种新型抗葡萄球菌药物。

DESCRIPTION (provided by applicant): 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 my laboratory. It is likely that the resistance mechanism involves several mutations and is multifaceted. I propose to study the mechanism of S. aureus vancomycin resistance in laboratory and clinical strains. I will study the composition and structure of peptidoglycan, and teichoic acid and lipoteichoic acid in GISA strains, and attempt to understand the mechanism of decreased autolytic activity observed in such strains. Cell wall alterations appear to be involved in vancomycin resistance. I will attempt to understand the increased NaC1-sensitivitv of GISA strains through studying the accumulation of compatible solutes. and whether Na+ ions accumulate intracellularly to growth inhibitory levels upon NaCl stress. Limited studies toward understanding the genetic basis of vancomycin will be undertaken. Nucleotide sequence analysis of cloned selected genes that physiological studies indicate may be altered in GISA strains will be carried out. 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 agent.