Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus.
Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus.
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DOI：
10.1172/jci16876
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发表时间：
2003-07
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通讯作者：
L. I. Kupferwasser;M. Yeaman;C. Nast;D. Kupferwasser;Y. Xiong;M. Palma;A. Cheung;A. Bayer
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文献类型：
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作者：
L. I. Kupferwasser;M. Yeaman;C. Nast;D. Kupferwasser;Y. Xiong;M. Palma;A. Cheung;A. Bayer
阿司匹林先前已被证明通过抗血小板和抗微生物机制降低实验性心内膜炎中金黄色葡萄球菌的体内毒力。在本研究中，阿司匹林的主要体内代谢物水杨酸减轻了临床和实验室金黄色葡萄球菌的两个重要毒力表型：α-溶血素分泌和体外纤维连接蛋白结合。此外，水杨酸还降低了α-溶血素基因启动子hla和纤维连接蛋白基因启动子fnbA的表达。转录分析、荧光分析和流式细胞术显示了水杨酸介导的应激反应基因SIGB激活的证据。SIGB可抑制的全球调节子SarA和全球调节子agr的表达也被水杨酸抑制，相应地，在体外，Hla和fnbA基因的表达降低。对实验性心内膜炎的研究证实了SARA和SIGB在体内介导水杨酸的抗葡萄球菌作用中的关键作用。因此，阿司匹林有可能通过下调金黄色葡萄球菌体内关键的全球调节基因和结构基因，从而取消相关的毒力表型，成为治疗金黄色葡萄球菌血管内感染的辅助治疗药物。
Aspirin has been previously shown to reduce the in vivo virulence of Staphylococcus aureus in experimental endocarditis, through antiplatelet and antimicrobial mechanisms. In the present study, salicylic acid, the major in vivo metabolite of aspirin, mitigated two important virulence phenotypes in both clinical and laboratory S. aureus strains: alpha-hemolysin secretion and fibronectin binding in vitro. In addition, salicylic acid reduced the expression of the alpha-hemolysin gene promoter, hla, and the fibronectin gene promoter, fnbA. Transcriptional analysis, fluorometry, and flow cytometry revealed evidence of salicylic acid-mediated activation of the stress-response gene sigB. Expression of the sigB-repressible global regulon sarA and the global regulon agr were also mitigated by salicylic acid, corresponding to the reduced expression of the hla and fnbA genes in vitro. Studies in experimental endocarditis confirmed the key roles of both sarA and sigB in mediating the antistaphylococcal effects of salicylic acid in vivo. Therefore, aspirin has the potential to be an adjuvant therapeutic agent against endovascular infections that result from S. aureus, by downmodulating key staphylococcal global regulons and structural genes in vivo, thus abrogating relevant virulence phenotypes.