The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis.
The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis.
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DOI：
10.1093/infdis/jiad577
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发表时间：
2024-01
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通讯作者：
Yanqiong Xiong;Yi Li;Mariya I. Goncheva;Ahmed M Elsayed;Fengli Zhu;Liang Li;W. Abdelhady;Ronald S. Flannagan;M. Yeaman;Arnold S. Bayer;D. Heinrichs
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作者：
Yanqiong Xiong;Yi Li;Mariya I. Goncheva;Ahmed M Elsayed;Fengli Zhu;Liang Li;W. Abdelhady;Ronald S. Flannagan;M. Yeaman;Arnold S. Bayer;D. Heinrichs
背景金黄色葡萄球菌是危及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，特别是由耐甲氧西林菌株（MRSA）引起的感染，其特点是治疗选择有限，发病率和死亡率高。在此，我们研究了嘌呤生物合成阻遏物PurR在MRSA所致实验性IE中毒力因子表达和万古霉素（货车）治疗结果中的作用。结果purR突变株中purF表达增强，嘌呤代谢中间产物产生增加，证实了purR介导的嘌呤生物合成抑制。此外，增强表达的转录调节因子，sigB和sarA，其关键的下游毒力基因（如，fnbA，和HLA）证明在purR突变体在体外和感染的心脏赘生物。此外，purR缺陷增强fnbA/fnbB转录，翻译成增加纤连蛋白粘附与野生型和purR互补菌株。值得注意的是，purR突变体在IE模型中货车治疗后对靶组织MRSA负荷的显著降低是难治的。结论：这些发现表明，嘌呤生物合成途径交叉的毒力因子表达和在货车治疗过程中的体内持久性的协调，并可能代表一种新的抗菌药物的发展目标MRSA的途径。
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.