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STAPHYLOCOCCAL VANCOMYCIN AND METHICILLIN RESISTANCE

葡萄球菌万古霉素和甲氧西林耐药性

基本信息

批准号：
6286159
负责人：
BRIAN JAMES WILKINSON
金额：
$ 19.33万
依托单位：
ILLINOIS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2003-09-29
项目状态：
已结题

项目摘要

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.

描述(改编自申请人摘要)：当务之急严重的金黄色葡萄球菌病，如菌血症和传染性心内膜炎是用有效的抗菌剂积极治疗的。这些疾病的死亡率分别为80%和100%。抗生素出现之前的时代。大多数医院的金黄色葡萄球菌菌株现在都是耐甲氧西林(MRSA)，这类菌株通常对多种其他抗生素。糖肽抗生素万古霉素是唯一的残留的抗生素，金黄色葡萄球菌对这些抗生素仍然一致敏感。最近，在患者长期服用万古霉素的过程中，出现了对万古霉素耐药的菌株。万古霉素治疗(所谓糖肽-中间敏感金黄色葡萄球菌) 或GISA菌株)。当务之急是我们必须了解这类菌株对万古霉素耐药。万古霉素耐药菌株已经被在调查人员实验室中选择的步骤。很可能，抵抗运动机制涉及多个突变，是多方面的。调查人员建议研究金黄色葡萄球菌万古霉素和甲氧西林的作用机制实验室和临床菌株的耐药性，他们的工作被组织成三个主要研究方向：一、万古霉素的表型研究抗药性；ii.万古霉素抗药性的基因研究；以及iii.胁迫甲氧西林和万古霉素耐药相关基因和蛋白的表达。在i中，他们将研究肽聚糖、磷壁酸的组成和结构。和脂磷壁酸，并试图了解其作用机制在这些菌株中观察到自溶活性降低。他们将尝试通过研究GISA菌株对盐的敏感性来了解GISA菌株对盐的敏感性增加相容溶质的积累，以及Na+离子是否积累细胞内对盐胁迫的生长抑制水平。在II中，他们将试图通过研究发现万古霉素耐药的遗传基础转座子诱变研究，直接克隆与万古霉素耐药性及其靶标的克隆和核苷酸序列分析 I研究表明在万古霉素耐药性中起作用的基因上面。在第三阶段，他们将研究细胞壁抗生素应激基因和甲氧西林和万古霉素耐药相关蛋白的表达蛋白质组学方法，使用基因芯片技术的转录图谱，并通过选择性捕获转录序列。预计这些研究将将导致控制对甲氧西林耐药和万古霉素耐药金黄色葡萄球菌感染，并形成发展的基础新型抗葡萄球菌药物。