VraT/YvqF Is Required for Methicillin Resistance and Activation of the VraSR Regulon in Staphylococcus aureus
VraT/YvqF Is Required for Methicillin Resistance and Activation of the VraSR Regulon in Staphylococcus aureus
复制标题
DOI：
10.1128/aac.01651-12
复制
发表时间：
2013-01-01
影响因子：
4.9
通讯作者：
Daum, Robert S.
中科院分区：
文献类型：
--
作者：
Boyle-Vavra, Susan;Yin, Shouhui;Daum, Robert S.
金黄色葡萄球菌感染是由对所有形式的青霉素耐药的菌株引起的，即所谓的耐甲氧西林金黄色葡萄球菌（MRSA）菌株，已经变得很常见。对抗MRSA感染的一种策略是使用使MRSA对甲氧西林重新敏感的化合物。金黄色葡萄球菌对不同种类的细胞壁抑制抗生素（如甲氧西林）有反应，利用双组分调节系统VraSR （vra）上调或下调一组基因（细胞壁刺激因子），这可能有助于对这些抗生素产生耐药性。因此，VraS和VraR突变降低了对甲氧西林、万古霉素和达托霉素细胞壁抗菌剂的耐药性。vraS和vraR一起编码在另外两个基因下游的转录本上，我们称之为vraU和vraT（以前称为yvqF）。通过在USA300 MRSA临床分离物中产生vraU和vraT的非极性缺失，我们证明vraT对于体外甲氧西林耐药的最佳表达是必要的，而vraU对于该表型不是必需的。在肺和皮肤感染小鼠模型中，vraT的缺失也改善了oxacillin治疗的结果。由于反式表达的vraT不补充vra操纵子缺失，我们得出结论，vraT不会使抗菌药物失活。全基因组转录微阵列实验表明，VraT通过在vrasr介导的细胞壁刺激中发挥必要的调节作用来促进抗性。我们的数据证明，VraTSR包含一个新的三组分调控系统，需要促进金黄色葡萄球菌对细胞壁剂的抗性。我们还提供了第一个使用VraT作为唯一靶点使MRSA对β -内酰胺重新敏感的体内原理证明。
Staphylococcus aureus infections caused by strains that are resistant to all forms of penicillin, so-called methicillin-resistant S. aureus (MRSA) strains, have become common. One strategy to counter MRSA infections is to use compounds that resensitize MRSA to methicillin. S. aureus responds to diverse classes of cell wall-inhibitory antibiotics, like methicillin, using the two-component regulatory system VraSR (vra) to up- or downregulate a set of genes (the cell wall stimulon) that presumably facilitates resistance to these antibiotics. Accordingly, VraS and VraR mutations decrease resistance to methicillin, vancomycin, and daptomycin cell wall antimicrobials. vraS and vraR are encoded together on a transcript downstream of two other genes, which we call vraU and vraT (previously called yvqF). By producing nonpolar deletions in vraU and vraT in a USA300 MRSA clinical isolate, we demonstrate that vraT is essential for optimal expression of methicillin resistance in vitro, whereas vraU is not required for this phenotype. The deletion of vraT also improved the outcomes of oxacillin therapy in mouse models of lung and skin infection. Since vraT expressed in trans did not complement a vra operon deletion, we conclude that VraT does not inactivate the antimicrobial. Genome-wide transcriptional microarray experiments reveal that VraT facilitates resistance by playing a necessary regulatory role in the VraSR-mediated cell wall stimulon. Our data prove that VraTSR comprise a novel three-component regulatory system required to facilitate resistance to cell wall agents in S. aureus. We also provide the first in vivo proof of principle for using VraT as a sole target to resensitize MRSA to beta-lactams.