Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery

Pathogens
Iram K IqbalAshwani Kumar

Abstract

Mycobacterium tuberculosis (Mtb) exhibits remarkable metabolic flexibility that enables it to survive a plethora of host environments during its life cycle. With the advent of bedaquiline for treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of Mtb on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents. This includes targeting NADH dehydrogenase by phenothiazine derivatives, menaquinone biosynthesis by DG70 and other compounds, terminal oxidase by imidazopyridine amides and ATP synthase by diarylquinolines. Importantly, oxidative phosphorylation also plays a critical role in the survival of persisters. Thus, inhibitors of oxidative phosphorylation can synergize with frontline TB drugs to shorten the course of treatment. In this review, we discuss the oxidative phosphorylation pathway and development of its inhibitors in detail.

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Citations

Aug 21, 2019·BMC Genomics·Izabela Coimbra IbraimVasco Azevedo
Oct 18, 2019·Antioxidants & Redox Signaling·Parminder Singh MaviAshwani Kumar
Jul 19, 2018·Frontiers in Microbiology·Diana MachadoMarco Pieroni
Nov 9, 2018·Oxidative Medicine and Cellular Longevity·Madhur D ShastriRonan F O'Toole
Nov 19, 2019·Progress in Biophysics and Molecular Biology·Ludovica Mascolo, Dirk Bald
Dec 18, 2020·Frontiers in Cellular and Infection Microbiology·Sapna BajeliAshwani Kumar
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Jan 5, 2022·Current Microbiology·Karen L F Alvarez-ErasoAndres Baena

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Methods Mentioned

BETA
single cell microscopy
surface plasmon resonance

Clinical Trials Mentioned

NCT02858973

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