Quinone skeleton as a new class of irreversible inhibitors against Staphylococcus aureus sortase A
Quinone skeleton as a new class of irreversible inhibitors against Staphylococcus aureus sortase A
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DOI：
10.1016/j.bmcl.2018.04.005
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发表时间：
2018-06-01
影响因子：
2.7
通讯作者：
Yang, Cai-Guang
中科院分区：
文献类型：
--
作者：
Hou, Xiaochen;Wang, Meining;Yang, Cai-Guang
分选酶A（SrtA）将表面蛋白锚定到细胞壁并在感染期间辅助生物膜形成，其作为重要革兰氏阳性病原体（例如金黄色葡萄球菌）的关键毒力因子发挥作用。目前，研究人员需要一种方法来验证SrtA是否是机制中常规抗生素靶标的可药用靶标替代品。在这项研究中，我们进行了高通量筛选，并确定了一类新的潜在的抑制剂的S。金黄色葡萄球菌SrtA，其衍生自天然产物并且含有醌骨架。化合物283作为共价烷基化SrtA的活性位点Cysl84的不可逆抑制剂起作用。NMR分析证实了小分子抑制剂对SrtA蛋白的直接相互作用。蛋白A（SpA）的锚定细胞壁和生物膜的形成显着减弱时，。在抑制剂存在下培养金黄色葡萄球菌纽曼菌株。我们的研究表明，化合物283可能是一个潜在的打击，为开发新的抗毒力剂，对S。金黄色葡萄球菌感染的共价靶向SrtA。(C)2018爱思唯尔有限公司版权所有
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 Cysl84 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 . 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. (C) 2018 Elsevier Ltd. All rights reserved.