ABSTRACT
The F1 FO -ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Bacterial Proton-Translocating ATPases/antagonists & inhibitors , Diarylquinolines/pharmacology , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Benzamides/chemistry , Benzamides/pharmacology , Benzamides/toxicity , Drug Synergism , Embryonic Stem Cells/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/toxicity , Humans , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium tuberculosis/enzymology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/toxicity , Structure-Activity RelationshipABSTRACT
Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (M. tuberculosis). WHO estimated that 10.4 million new (incident) TB cases worldwide in year 2016. The increased prevalence of drug resistant strains and side effects associated with the current anti-tubercular drugs make the treatment options more complicated. Hence, there are necessities to identify new drug candidates to fight against various sub-populations of M. tuberculosis with less or no toxicity/side effects and shorter treatment duration. Bacteriocins produced by lactic acid bacteria (LAB) attract attention of researchers because of its 'Generally recognized as safe' status. LAB and its bacteriocins possess an effective antimicrobial activity against various bacteria and fungi. Interestingly bacteriocins such as nisin and lacticin 3147 have shown antimycobacterial activity in vitro. As probiotics, LAB plays a vital role in promoting various health benefits including ability to modulate immune response against various infectious diseases. LAB and its metabolic products activate immune system and thereby limiting the M. tuberculosis pathogenesis. The protein and peptide engineering techniques paved the ways to obtain hybrid bacteriocin derivatives from the known peptide sequence of existing bacteriocin. In this review, we focus on the antimycobacterial property and immunomodulatory role of LAB and its metabolic products. Techniques for large scale synthesis of potential bacteriocin with multifunctional activity and enhanced stability are also discussed.
