嘌呤生物合成抑制剂 PurR 有助于耐甲氧西林金黄色葡萄球菌实验性心内膜炎对万古霉素的敏感性。
The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis.
机构信息
The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.
Department of Medicine, Division of Infectious Diseases, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.
出版信息
J Infect Dis. 2024 Jun 14;229(6):1648-1657. doi: 10.1093/infdis/jiad577.
BACKGROUND
Staphylococcus aureus is the most common cause of life-threatening endovascular infections, including infective endocarditis (IE). These infections, especially when caused by methicillin-resistant strains (MRSA), feature limited therapeutic options and high morbidity and mortality rates.
METHODS
Herein, we investigated the role of the purine biosynthesis repressor, PurR, in virulence factor expression and vancomycin (VAN) treatment outcomes in experimental IE due to MRSA.
RESULTS
The PurR-mediated repression of purine biosynthesis was confirmed by enhanced purF expression and production of an intermediate purine metabolite in purR mutant strain. In addition, enhanced expression of the transcriptional regulators, sigB and sarA, and their key downstream virulence genes (eg, fnbA, and hla) was demonstrated in the purR mutant in vitro and within infected cardiac vegetations. Furthermore, purR deficiency enhanced fnbA/fnbB transcription, translating to increased fibronectin adhesion versus the wild type and purR-complemented strains. Notably, the purR mutant was refractory to significant reduction in target tissues MRSA burden following VAN treatment in the IE model.
CONCLUSIONS
These findings suggest that the purine biosynthetic pathway intersects the coordination of virulence factor expression and in vivo persistence during VAN treatment, and may represent an avenue for novel antimicrobial development targeting MRSA.
背景
金黄色葡萄球菌是威胁生命的血管内感染的最常见原因，包括感染性心内膜炎（IE）。这些感染，尤其是由耐甲氧西林金黄色葡萄球菌（MRSA）引起的感染，治疗选择有限，发病率和死亡率高。
方法
在此，我们研究了嘌呤生物合成抑制剂 PurR 在 MRSA 引起的实验性 IE 中对毒力因子表达和万古霉素（VAN）治疗结果的作用。
结果
PurR 介导的嘌呤生物合成抑制通过增强 purF 表达和中间嘌呤代谢物的产生在 purR 突变株中得到证实。此外，在体外和感染的心脏赘生物中，PurR 突变体中证明了转录调节剂 sigB 和 sarA 及其关键下游毒力基因（如 fnbA 和 hla）的表达增强。此外，PurR 缺失增强了 fnbA/fnbB 的转录，与野生型和 PurR 互补株相比，增加了纤维连接蛋白的黏附。值得注意的是，在 IE 模型中，PurR 突变体在 VAN 治疗后对靶组织中 MRSA 负荷的显著减少具有抗性。
结论
这些发现表明，嘌呤生物合成途径与 VAN 治疗期间毒力因子表达和体内持续存在的协调有关，可能代表针对 MRSA 的新型抗菌药物开发的途径。
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