Mutated response regulator graR is responsible for phenotypic conversion of Staphylococcus aureus from heterogeneous vancomycin-intermediate resistance to vancomycin-intermediate resistance
Mutated response regulator graR is responsible for phenotypic conversion of Staphylococcus aureus from heterogeneous vancomycin-intermediate resistance to vancomycin-intermediate resistance
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DOI：
10.1128/aac.00534-07
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发表时间：
2008-01-01
影响因子：
4.9
通讯作者：
Hiramatsu, Keiichi
中科院分区：
文献类型：
--
作者：
Neoh, Hui-Min;Cui, Longzhu;Hiramatsu, Keiichi
耐甲氧西林金黄色葡萄球菌(MRSA)需要进行多步基因改造，才能达到万古霉素中间体金黄色葡萄球菌(VISA)对万古霉素的耐药性水平。在万古霉素耐药的发展过程中，观察到具有异质性万古霉素耐药的菌株，称为异源VISA。在研究具有代表性的异源VISA株Mu3的全基因组序列，并将其与密切相关的MRSA株Mu50(VISA)和N315(万古霉素敏感的金黄色葡萄球菌[VSSA])进行比较时，我们发现了graSR双组分调控系统的反应调节因子中的一个突变。引入突变的grar，命名为grar*，而不是完整的grar，命名为graRn，可以将Mu3的异源VISA表型转化为与Mu50相当的VISA表型。同样的方法并没有显著增加VSSA菌株N315对万古霉素的抗性，这表明GRAR*的表达只在异种VISA细胞获得VISA表型的生理环境中有效。有趣的是，GRAR*的过表达增加了MU3和N315对达托霉素的MIC，降低了N315对苯唑西林的MIC。
Multistep genetic alteration is required for methicillin-resistant Staphylococcus aureus (MRSA) to achieve the level of vancomycin resistance of vancomycin-intermediate S. aureus (VISA). In the progression of vancomycin resistance, strains with heterogeneous vancomycin resistance, designated hetero-VISA, are observed. In studying the whole-genome sequencing of the representative hetero-VISA strain Mu3 and comparing it with that of closely related MRSA strains Mu50 (VISA) and N315 (vancomycin-susceptible S. aureus [VSSA]), we identified a mutation in the response regulator of the graSR two-component regulatory system. Introduction of mutated graR, designated graR*, but not intact graR, designated graRn, could convert the hetero-VISA phenotype of Mu3 into a VISA phenotype which was comparable to that of Mu50. The same procedure did not appreciably increase the vancomycin resistance of VSSA strain N315, indicating that graR* expression was effective only in the physiological milieu of hetero-VISA cell to achieve a VISA phenotype. Interestingly, the overexpression of graR* increased the daptomycin MICs in both Mu3 and N315 and decreased the oxacillin MIC in N315.