Wang Lin, Bi Chongwei, Cai Hongjun, Liu Bingrun, Zhong Xiaobo, Deng Xuming, Wang Tiedong, Xiang Hua, Niu Xiaodi, Wang Dacheng
Key Laboratory of Zoonosis Research, Ministry of Education/Institute of Zoonosis/College of Veterinary Medicine, Jilin University Changchun, China.
College of Animal Science, Jilin University Changchun, China.
Front Microbiol. 2015 Oct 16;6:1031. doi: 10.3389/fmicb.2015.01031. eCollection 2015.
The emergence and wide spread of multi-drug resistant Staphylococcus aureus (S. aureus) requires the development of new therapeutic agents with alternative modes of action. Anti-virulence strategies are hoped to meet that need. Sortase A (SrtA) has attracted great interest as a potential drug target to treat infections caused by S. aureus, as many of the surface proteins displayed by SrtA function as virulence factors by mediating bacterial adhesion to specific organ tissues, invasion of host cells, and evasion of the host-immune responses. It has been suggested that inhibitors of SrtA might be promising candidates for the treatment and/or prevention of S. aureus infections. In this study, we report that chlorogenic acid (CHA), a natural compound that lacks significant anti-S. aureus activity, inhibit the activity of SrtA in vitro (IC50 = 33.86 ± 5.55 μg/ml) and the binding of S. aureus to fibrinogen (Fg). Using molecular dynamics simulations and mutagenesis assays, we further demonstrate that CHA binds to the binding sites of C184 and G192 in the SrtA. In vivo studies demonstrated that CHA prevent mice from S. aureus-induced renal abscess, resulting in a significant survival advantage. These findings indicate that CHA is a promising therapeutic compound against SrtA during S. aureus infections.
耐多药金黄色葡萄球菌（S. aureus）的出现和广泛传播，需要研发具有替代作用模式的新型治疗药物。抗毒力策略有望满足这一需求。分选酶A（SrtA）作为治疗金黄色葡萄球菌感染的潜在药物靶点，已引起了极大关注，因为SrtA展示的许多表面蛋白通过介导细菌与特定器官组织的粘附、宿主细胞的侵袭以及宿主免疫反应的逃避，发挥着毒力因子的作用。有人提出，SrtA抑制剂可能是治疗和/或预防金黄色葡萄球菌感染的有前景的候选药物。在本研究中，我们报告绿原酸（CHA），一种对金黄色葡萄球菌缺乏显著活性的天然化合物，在体外抑制SrtA的活性（IC50 = 33.86 ± 5.55 μg/ml）以及金黄色葡萄球菌与纤维蛋白原（Fg）的结合。使用分子动力学模拟和诱变分析，我们进一步证明CHA与SrtA中C184和G192的结合位点结合。体内研究表明，CHA可预防小鼠因金黄色葡萄球菌引起的肾脓肿，从而带来显著的生存优势。这些发现表明，CHA是在金黄色葡萄球菌感染期间针对SrtA的一种有前景的治疗化合物。
