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The mechanism of high methicillin resistance in Staphylococcus aureus

金黄色葡萄球菌对甲氧西林高度耐药的机制

基本信息

批准号：
18590438
负责人：
CUI Longzhu
金额：
$ 2.57万
依托单位：
Juntendo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Methicillin resistance in Staphylococcus aureus is due to the acquisition of the low-affinity penicillin binding protein, PBP2A, encoded by mecA. However, there is lack of correlation between resistance levels and amount of PBP2A production leading to the conclusion that resistance to high levels of methicillin depends, in addition to PBP2A, on chromosomally encoded factors that are responsible for the strain-specific differences in resistance. The present study aims to investigate the factors affecting high methicillin resistance in MRSA. The study was started with isolating a set of isogenic MRSA strains with different level of methicillin resistance, and their whole genome sequences were determined. By comparing the genome sequence among the set of strains, candidate genes involved in high methicillin-resistant phenotype were identified and evaluated. Secondly, the genes identified as high methicillin-resistance associated in both this and our previous study, such as hmrA, hmrB, mgrA, graF and msrA2, were overexpressed in S.aureus to rise the level of methicillin resistance, and their transcriptional profiles for whole genome scale were compared each other, then the commonly regulated genes were identified to clarify the regulatory network of high methicillin resistance (HMR). The study conclusions are : 1) Fully expression of two component regulator system vraSR is necessary for HMR ; 2) regulatory gene sarH1 is deeply involved in HMR phenotype and 3) a novel mechanism, regulatory flip-flop genome inversion for HMR, was identified whereby HMR can achieved without chromosome mutation, but the detail deeded to be investigated.

金黄色葡萄球菌耐甲氧西林是由于获得了低亲和力的青霉素结合蛋白PBP2A，该蛋白由mecA编码。然而，抗性水平与PBP2A产量之间缺乏相关性，这导致结论认为，除了PBP2A外，对高水平甲氧西林的抗性还取决于染色体编码的因素，这些因素导致了菌株特异性的抗性差异。本研究旨在探讨MRSA高甲氧西林耐药性的影响因素。本研究首先分离出一组不同甲氧西林耐药水平的等基因MRSA菌株，并测定其全基因组序列。通过比较各组菌株的基因组序列，鉴定并评价了高耐甲氧西林表型的候选基因。其次，将本研究与我们前期研究相关的高甲氧西林耐药基因hmrA、hmrB、mgrA、graF和msrA2在金黄色葡萄球菌中过表达，提高甲氧西林耐药水平，并在全基因组尺度上比较它们的转录谱，鉴定出常见的调控基因，明确高甲氧西林耐药（HMR）调控网络。研究结论为：1)HMR需要双组分调控系统vraSR的充分表达；2)调控基因sarH1与HMR表型密切相关；3)HMR的调控触发器基因组倒置（regulatory flip-flop genome inversion）是一种新的机制，HMR可以在不发生染色体突变的情况下实现，但其细节有待进一步研究。