Current Perspective of ATP Synthase Inhibitors in the Management of the Tuberculosis

• Published in: Current topics in medicinal chemistry Vol. 21; no. 18; p. 1623
• Main Authors: Divita, K M, Khatik, Gopal L
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-01-2021
• Subjects: Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Diarylquinolines - chemical synthesis; Diarylquinolines - chemistry; Diarylquinolines - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Molecular Structure; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Proton-Translocating ATPases - antagonists & inhibitors; Proton-Translocating ATPases - metabolism; Tuberculosis, Multidrug-Resistant - drug therapy; MDR-TB; ATP synthase; Inhibitor; Tuberculosis; XDR-TB; Bedaquiline
• ISSN: 1873-4294
• DOI: 10.2174/1568026621666210913122346

Tuberculosis is a life-threatening disease, and the drugs discovered during the era of 1950 and 1970 are found to be inefficient due to emergent MDR and XDR-TB. Tuberculosis is difficult to treat due to the development of antibiotic resistance. ATP synthase consists of two units, F1 and F0 units. These are present in the cytoplasm and membrane of mitochondria, respectively. F1 unit comprises of a, b, and c subunit while F0 subunit has α, β, γ, δ, ε subunits. Bedaquiline was the first approved ATP synthase inhibitor in 2012 by USFDA.
Recent literature from 2005-2020 were collected using Pubmed with the keywords ATP synthase inhibitor, bedaquiline derivatives, tuberculosis. The work describing detailed analyses of bedaquiline (BDQ) was included in the current work, and others were excluded.
ATP production occurs via the ATP synthase enzyme, leading to the growth and multiplication of mycobacteria. BDQ inhibits the mycobacterium ATP synthase enzyme, a heteropolymeric complex consisting of two subunits, but it does not interfere with mammalian ATP synthase. Bedaquiline (BDQ) has become a drug of choice in treating MDR-TB and helps in reducing the treatment span. Recently observed triple mutation as wtLeu59
→mtVal59
; wtIle66
→mtMet66
and wtGlu61
→mtAsp61
of ATP synthase led to decrease BDQ binding affinity; thus, researchers are putting efforts for its newer derivative discovery.
ATP synthase inhibitor could be an alternative approach for better treatment of tuberculosis. Herein we discussed the recent advancements in the development of newer analogues of BDQ with its future perspectives.