Mycobacterium tuberculosis F-ATP Synthase Inhibitors and Targets

Mycobacteria tuberculosis (Mtb) infection causes tuberculosis (TB). TB is one of the most intractable infectious diseases, causing over 1.13 million deaths annually. Under harsh growing conditions, the innate response of mycobacteria is to shut down its respiratory metabolism to a basal level, transit into a dormant, non-replicating phase to preserve viability, and establish latent infection. Mtb utilizes non-canonical regulatory mechanisms, such as alternative oxidase pathways, to survive in low oxygen/nutrient conditions. The bacterium’s survival in its native microenvironmental niches is aided by its ability to evolve mutations to drug binding sites, enhance overexpression of various enzymes that activate β-lactam antibiotics hydrolysis, or stimulate efflux pathways to ward off the effect of antibiotics. Bedaquiline and its 3,5-dialkoxypyridine analogs, sudapyridine and squaramide S31f, have been shown to be potent Mtb F₁F_O-ATP synthase inhibitors of replicating and non-replicating Mtb and have brought oxidative phosphorylation into focus as an anti-TB target. In this review, we attempt to highlight non-canonical structural and regulatory pathogen-specific epitopes of the F₁-domain, ligand development on such sites, structural classes of inhibitors targeting the Fo-domain, and alternative respiratory metabolic responses that Mtb employs in response to bedaquiline to ensure its survival and establish latent infection.