State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China; University of the Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China.
Bioorg Med Chem Lett. 2018 Jun 1;28(10):1864-1869. doi: 10.1016/j.bmcl.2018.04.005. Epub 2018 Apr 4.
Sortase A (SrtA) anchors surface proteins to the cell wall and aids biofilm formation during infection, which functions as a key virulence factor of important Gram-positive pathogens, such as Staphylococcus aureus. At present researchers need a way in which to validate whether or not SrtA is a druggable target alternative to the conventional antibiotic targets in the mechanism. In this study, we performed a high-throughput screening and identified a new class of potential inhibitors of S. aureus SrtA, which are derived from natural products and contain the quinone skeleton. Compound 283 functions as an irreversible inhibitor that covalently alkylates the active site Cys184 of SrtA. NMR analysis confirms the direct interaction of the small-molecule inhibitor towards SrtA protein. The anchoring of protein A (SpA) to the cell wall and the biofilm formation are significantly attenuated when the S. aureus Newman strain is cultured in the presence of inhibitor. Our study indicates that compound 283 could be a potential hit for the development of new anti-virulence agents against S. aureus infections by covalently targeting SrtA.
金黄色葡萄球菌表面蛋白转肽酶 A（SrtA）将表面蛋白锚定在细胞壁上，并有助于感染期间生物膜的形成，它是金黄色葡萄球菌等重要革兰氏阳性病原体的关键毒力因子。目前，研究人员需要一种方法来验证 SrtA 是否是一种可成药的替代传统抗生素作用机制的靶点。在这项研究中，我们进行了高通量筛选，鉴定出了一类新型金黄色葡萄球菌 SrtA 的潜在抑制剂，这些抑制剂来源于天然产物并含有醌骨架。化合物 283 是一种不可逆抑制剂，可使 SrtA 的活性位点半胱氨酸 184 发生烷基化共价结合。NMR 分析证实了小分子抑制剂与 SrtA 蛋白的直接相互作用。当金黄色葡萄球菌 Newman 菌株在抑制剂存在的情况下培养时，蛋白 A（SpA）与细胞壁的锚定和生物膜的形成显著减弱。我们的研究表明，化合物 283 可以通过共价靶向 SrtA 成为开发针对金黄色葡萄球菌感染的新型抗毒力药物的潜在候选药物。
