ABSTRACT
Tuberculosis is the second leading cause of death by infectious disease worldwide after COVID-19. Mycobacterium tuberculosis, which causes tuberculosis, is showing alarming levels of resistance to first-line antibiotics, jeopardizing efforts to eradicate the disease. Research is underway to develop new, safer drugs to treat drug resistant tuberculosis. One of these breakthrough drugs is bedaquiline, which targets the mycobacterial ATP synthase, an essential enzyme in mycobacteria. The success of bedaquiline, which has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis, demonstrates the importance of the mycobacterial ATP synthase as a key drug target against M. tuberculosis. Since the discovery of bedaquiline in 2005, there has been a renewed interest in developing new and improved mycobacterial ATP synthase inhibitors. We have determined electron cryomicroscopy structures of M. smegmatis ATP synthase in complex with inhibitors. We provide detailed mechanistic and structural insights into the mode of action of these compounds, which will support medicinal chemistry efforts to design new tuberculosis drugs. Our work reveals new inhibitor binding sites in the enzyme, opening the route for development of new classes of compounds and improved inhibitors. Copyright © 2022