Emerging opportunities of exploiting mycobacterial electron transport chain pathway for drug-resistant tuberculosis drug discovery.

Introduction: Tuberculosis (TB) is a leading infectious disease worldwide whose chemotherapy is challenged by the continued rise of drug resistance. This epidemic urges the need to discover anti-TB drugs with novel modes of action.Areas covered: The mycobacterial electron transport chain (ETC) pathway represents a hub of anti-TB drug targets. Herein, the authors highlight the various targets within the mycobacterial ETC and highlight some of the promising ETC-targeted drugs and clinical candidates that have been discovered or repurposed. Furthermore, recent breakthroughs in the availability of X-ray and/or cryo-EM structures of some targets are discussed, and various opportunities of exploiting these structures for the discovery of new anti-TB drugs are emphasized.Expert opinion: The drug discovery efforts targeting the ETC pathway have led to the FDA approval of bedaquiline, a FOF1-ATP synthase inhibitor, and the discovery of Q203, a clinical candidate drug targeting the mycobacterial cytochrome bcc-aa3 supercomplex. Moreover, clofazimine, a proposed prodrug competing with menaquinone for its reduction by mycobacterial NADH dehydrogenase 2, has been repurposed for TB treatment. Recently available structures of the mycobacterial ATP synthase C9 rotary ring and the cytochrome bcc-aa3 supercomplex represent further opportunities for the structure-based drug design (SBDD) of the next-generation of inhibitors against Mycobacterium tuberculosis.