Structure-based design, synthesis, and study of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents
Structure-based design, synthesis, and study of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents
复制标题
DOI：
10.1021/jm049141s
复制
发表时间：
2005-03-10
影响因子：
7.3
通讯作者：
Chu, SS
中科院分区：
文献类型：
--
作者：
Nie, Z;Perretta, C;Chu, SS
脂肪酸的生物合成是细菌生存所必需的。该生物合成途径的组分已被确定为开发新抗菌剂的有吸引力的靶点。FabH，β-酮脂酰-ACP合酶III，是一个特别有吸引力的靶标，因为它是脂肪酸生物合成起始的核心，并且在革兰氏阳性和阴性细菌中高度保守。抑制FabH酶活性的小分子有可能成为一类新型选择性、无毒、广谱抗菌剂的候选者。利用这些高度保守的活性位点的晶体学结构信息和基于结构的药物设计原理，开发了苯甲酰氨基苯甲酸系列化合物作为FabH的有效抑制剂。这类抑制剂对革兰氏阳性和选定的革兰氏阴性微生物表现出很强的抗菌活性。
Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Small molecules that inhibit FabH enzymatic activity have the potential to be candidates within a novel class of selective, nontoxic, broad-spectrum antibacterials. Using crystallographic structural information on these highly conserved active sites and structure based drug design principles, a benzoylaminobenzoic acid series of compounds was developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity against Gram-positive and selected Gram-negative organisms.