Nie Zhe, Perretta Carin, Lu Jia, Su Ying, Margosiak Stephen, Gajiwala Ketan S, Cortez Joseph, Nikulin Victor, Yager Kraig M, Appelt Krzysztof, Chu Shaosong
Departments of Medicinal Chemistry, Protein Biochemistry and Structural Biology, Quorex Pharmaceuticals Inc., 1890 Rutherford Road, Suite 200, Carlsbad, CA 92008, USA.
J Med Chem. 2005 Mar 10;48(5):1596-609. doi: 10.1021/jm049141s.
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.
脂肪酸生物合成对于细菌存活至关重要。该生物合成途径的组分已被确定为开发新型抗菌剂的有吸引力的靶点。β-酮脂酰-ACP合酶III（FabH）是一个特别有吸引力的靶点，因为它是脂肪酸生物合成起始的关键，并且在革兰氏阳性菌和革兰氏阴性菌中高度保守。抑制FabH酶活性的小分子有可能成为一类新型选择性、无毒、广谱抗菌剂的候选物。利用这些高度保守活性位点的晶体学结构信息和基于结构的药物设计原则，开发了一系列苯甲酰氨基苯甲酸类化合物作为FabH的强效抑制剂。这类抑制剂对革兰氏阳性菌和某些革兰氏阴性菌显示出强大的抗菌活性。
