Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India.
Division of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, 226 031, Uttar Pradesh, India.
Eur J Med Chem. 2020 Dec 15;208:112757. doi: 10.1016/j.ejmech.2020.112757. Epub 2020 Aug 23.
Development of new anti-bacterial agents acting upon underexploited targets and thus evading known mechanisms of resistance is the need of the hour. The highly conserved and distinct bacterial fatty acid biosynthesis pathway (FAS-II), presents a validated and yet relatively underexploited target for drug discovery. FabI and its isoforms (FabL, FabK, FabV and InhA) are essential enoyl-ACP reductases present in several microorganisms. In addition, the components of the FAS-II pathway are distinct from the multi-enzyme FAS-I complex found in mammals. Thus, inhibition of FabI and its isoforms is anticipated to result in broad-spectrum antibacterial activity. Several research groups from industry and academic laboratories have devoted significant efforts to develop effective FabI-targeting antibiotics, which are currently in various stages of clinical development for the treatment of multi-drug resistant bacterial infections. This review summarizes all the natural as well as synthetic inhibitors of gram-positive and gram-negative enoyl ACP reductases (FabI). The knowledge of the reported inhibitors can aid in the development of broad-spectrum antibacterials specifically targeting FabI enzymes from S. aureus, S. epidermidis, B. anthracis, B. cereus, E. coli, P. aeruginosa, P. falciparum and M. tuberculosis.
开发针对利用不足的靶点的新型抗菌药物，从而规避已知的耐药机制，是当前的迫切需求。高度保守且独特的细菌脂肪酸生物合成途径 (FAS-II) 是一个经过验证但尚未得到充分利用的药物发现靶点。FabI 及其同工酶（FabL、FabK、FabV 和 InhA）是几种微生物中必需的烯酰-ACP 还原酶。此外，FAS-II 途径的组成部分与哺乳动物中发现的多酶 FAS-I 复合物不同。因此，抑制 FabI 及其同工酶预计会产生广谱抗菌活性。来自工业和学术实验室的几个研究小组投入了大量精力来开发有效的 FabI 靶向抗生素，这些抗生素目前处于临床开发的各个阶段，用于治疗多药耐药细菌感染。本综述总结了革兰氏阳性和革兰氏阴性烯酰 ACP 还原酶 (FabI) 的所有天然和合成抑制剂。对已报道抑制剂的了解有助于开发针对金黄色葡萄球菌、表皮葡萄球菌、炭疽芽孢杆菌、蜡样芽孢杆菌、大肠杆菌、铜绿假单胞菌、疟原虫和结核分枝杆菌的 FabI 酶的广谱抗菌药物。
