Figure. Cryo-electron microscopy structure of Mycobacterium tuberculosis ATP synthase bound to BDQ

Supported by the National Natural Science Foundation of China (Grant No. 82222042、32100976 and 32394010), Prof. Hongri Gong and Academician Zihe Rao from Nankai University, Assoc. Prof. Fengjiang Liu from Guangzhou Laboratory, and Assoc. Prof. Yan Gao from ShanghaiTech University cooperated and made progress in the molecular mechanism by which BDQ and its analogue TBAJ-587 inhibit the ATP synthase of Mycobacterium tuberculosis. The related research was titled " Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587" and published in Nature on July 3, 2024.

The link to the paper is: https://www.nature.com/articles/s41586-024-07605-8.

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, which mainly attacks the lungs and can lead to death in serious cases, so being one of the major public health problems of global concern. BDQ, an inhibitor of ATP synthase of Mycobacterium tuberculosis, can effectively inhibit the growth of Mycobacterium tuberculosis. As the first new anti-tuberculosis drug developed globally and launched in nearly 50 years, BDQ has been listed by the World Health Organization as the first-choice drug in the long-term treatment of tuberculosis resistant to rifampicin or multiple drugs. However, studies have found that BDQ increases the risk of cardiac arrhythmias in patients due to its interaction with the hERG potassium ion channel, in addition to having potential cross-inhibitory activity on human ATP synthase. Therefore, it is of great significance to reveal the mechanism of action of BDQ as well as the molecular mechanism to inhibit the ATP synthase in humans in the development of novel inhibitors for ATP synthase of Mycobacterium tuberculosis, thus reducing the side effects of tuberculosis treatment.

The research team used the gene knock-in/knock-out & gene overexpression strategy in combination with affinity chromatography and gel filtration chromatography to obtain a uniform, stable and active protein sample of Mycobacterium tuberculosis ATP synthase through Mycobacterium smegmatis. They determined the high-resolution cryo-electron microscopy structure of Mycobacterium tuberculosis ATP synthase bound to BDQ and its analogue TBAJ-587. The research found that BDQ strongly interacts with Mycobacterium tuberculosis ATP synthase through quinolinyl (A unit) and dimethylamino (D unit) and binds to multiple sites in the transmembrane domain, preventing the rotation of the c-ring of ATP synthase in the transmembrane domain, blocking proton transport, preventing ATP synthesis, achieving the goal of Mycobacterium tuberculosis starved to death. TBAJ-587 have similar modes of action.

They also analyzed the cryo-electron microscopy structure of human ATP synthase bound to BDQ with results showing that the redesigned TBAJ-587 which have optimization on the B and C units in BDQ only reduces the risk of cardiac arrhythmias caused by the interaction with hERG protein. Optimizing the A unit may reduce the interaction with human ATP synthase, thereby avoiding potential health risks in clinical treatment.

This research elucidates the molecular mechanism by which BDQ and its analogue TBAJ-587 inhibit the ATP synthase of Mycobacterium tuberculosis, and reveals the mechanism of their cross-reaction with ATP synthase in humans, which is of great significance for the development of new generation of highly selective drugs for tuberculosis.