ATP Synthase, an Emerging Target in TB Drug Discovery: Review of SAR and Clinical Pharmacology of Diarylquinoline Inhibitors

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is one of the leading causes of mortality worldwide, with an estimated 1.5 million deaths annually. The majority of infection cases are reported from the Southeast Asian region, including India. After the discovery of Streptomycin in 1943 and its anti-tubercular activity in 1945, drug discovery efforts identified Isoniazid, Ethambutol, and Rifampin as TB-actives. However, over the years, these drugs have been rendered ineffective due to genetic mutations in mycobacterial strains. This has shifted drug discovery efforts towards identifying new targets and drugs for drug-resistant forms of bacteria. ATP synthase was identified as one of the key targets of MDR-TB. This review provides key insights into the ATP synthase target, structure activity relationship studies (SAR) of diarylquinoline class of inhibitors and their clinical relevance for treating MDR-TB.