南开大学贡红日等研究人员合作揭示BDQ和TBAJ-587对结核分枝杆菌及人类ATP合酶的抑制作用。这一研究成果于2024年7月3日在线发表在国际学术期刊《自然》上。

研究人员展示了结核分枝杆菌ATP合酶在BDQ和TBAJ-587结合与未结合情况下的冷冻电镜结构，以及与BDQ结合的人类ATP合酶结构。这两种抑制剂与分枝杆菌ATP合酶的a亚基和c环在领位点、仅c位点和滞后位点相互作用，显示出BDQ和TBAJ-587具有相似的作用方式。这些化合物的喹啉基和二甲氨基单元与蛋白质进行了广泛的接触。

与BDQ结合的人类ATP合酶结构显示，BDQ结合位点类似于观察到的分枝杆菌ATP合酶的领位点，喹啉基单元也与人类酶相互作用广泛。这项研究将增进研究人员对于人类ATP合酶和分枝杆菌ATP合酶在BDQ结合模式方面的相似性和差异性的理解，并有助于合理设计新型二芳基喹啉类抗结核药物。

据介绍，diarylquinoline抗结核药物bedaquiline（BDQ），作为首个类别的药物，及其类似物TBAJ-587通过抑制ATP合酶阻止分枝杆菌的生长和增殖。然而，BDQ也抑制人类ATP合酶。目前尚不清楚这些化合物如何与分枝杆菌ATP合酶或人类ATP合酶相互作用。

附：英文原文

Title: Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587

Author: Zhang, Yuying, Lai, Yuezheng, Zhou, Shan, Ran, Ting, Zhang, Yue, Zhao, Ziqing, Feng, Ziyan, Yu, Long, Xu, Jinxu, Shi, Kun, Wang, Jianyun, Pang, Yu, Li, Liang, Chen, Hongming, Guddat, Luke W., Gao, Yan, Liu, Fengjiang, Rao, Zihe, Gong, Hongri

Issue&Volume: 2024-07-03

Abstract: Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. However, BDQ also inhibits human ATP synthase3. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers’ understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.

DOI: 10.1038/s41586-024-07605-8

Source: https://www.nature.com/articles/s41586-024-07605-8