化学
细胞色素
氧化酶试验
结核分枝杆菌
细胞色素c
细胞色素c氧化酶
生物化学
立体化学
酶
肺结核
细胞凋亡
医学
病理
作者
Yang Zhou,Min Shao,Weiwei Wang,Chen‐Yi Cheung,Yu Wu,Hang Yu,Xianglong Hu,Gregory M. Cook,Huanfa Gong,Xiaoyun Lu
标识
DOI:10.1016/j.ejmech.2022.114896
摘要
The cytochrome bcc-aa3 oxidase (Cyt-bcc) of Mycobacterium tuberculosis (Mtb) is a promising anti-tuberculosis target. However, when Cyt-bcc is inhibited, cytochrome bd terminal oxidase (Cyt-bd) can still maintain the activity of the respiratory chain and drive ATP synthesis. Through virtual screening and biological validation, we discovered two FDA-approved drugs, ivacaftor and roquinimex, exhibited moderate binding affinity to Cyt-bd. Structural modifications of them led to 1-hydroxy-2-methylquinolin-4(1H)-one derivatives as potent new Cyt-bd inhibitors. Compound 8d binds to Cyt-bd with a Kd value of 4.17 μM and inhibits the growth of the Cyt-bcc knock-out strain (ΔqcrCAB, Cyt-bd+) with a MIC value of 6.25 μM. The combination of 8d with the Cyt-bcc inhibitor Q203 completely inhibited oxygen consumption of the wild-type strain and the inverted-membrane vesicles expressing M. tuberculosis Cyt-bd (ΔcydAB::MtbCydAB+). Our study provides a promising starting point for the development of novel dual chemotherapies for tuberculosis.
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