Guan Xiang-Na, Zhang Tao, Yang Teng, Dong Ze, Yang Song, Lan Lefu, Gan Jianhua, Yang Cai-Guang
Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China
University of the Chinese Academy of Sciences Beijing 100049 China.
RSC Med Chem. 2021 Nov 1;13(2):138-149. doi: 10.1039/d1md00316j. eCollection 2022 Feb 23.
The housekeeping sortase A (SrtA), a membrane-associated cysteine transpeptidase, is responsible for anchoring surface proteins to the cell wall peptidoglycan in Gram-positive bacteria. This process is essential for the regulation of bacterial virulence and pathogenicity. Therefore, SrtA is considered to be an ideal target for antivirulence therapy. In this study, we report that ML346, a compound with a barbituric acid and cinnamaldehyde scaffold, functions as an irreversible inhibitor of SrtA (SrtA) and SrtA (SrtA) at low micromolar concentrations. According to our X-ray crystal structure of the SrtA/ML346 complex (Protein Data Bank ID: 7V6K), ML346 covalently modifies the thiol group of Cys208 in the active site of SrtA. Importantly, ML346 significantly attenuated the virulence phenotypes of and exhibited inhibitory effects on larva infection caused by . Collectively, our results indicate that ML346 has potential for development as a covalent antivirulence agent for treating infections, including methicillin-resistant .
管家分选酶A（SrtA）是一种与膜相关的半胱氨酸转肽酶，负责将表面蛋白锚定到革兰氏阳性菌的细胞壁肽聚糖上。这一过程对于细菌毒力和致病性的调节至关重要。因此，SrtA被认为是抗毒力治疗的理想靶点。在本研究中，我们报告了一种具有巴比妥酸和肉桂醛支架的化合物ML346，在低微摩尔浓度下作为SrtA的不可逆抑制剂发挥作用。根据我们的SrtA/ML346复合物的X射线晶体结构（蛋白质数据库ID：7V6K），ML346共价修饰SrtA活性位点中Cys208的巯基。重要的是，ML346显著减弱了[具体细菌名称1]的毒力表型，并对[具体细菌名称2]引起的幼虫感染表现出抑制作用。总体而言，我们的结果表明，ML346有潜力开发成为一种用于治疗[具体细菌名称1]感染（包括耐甲氧西林[具体细菌名称1]）的共价抗毒力药物。
