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Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery

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...

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Autores principales: Iqbal, Iram Khan, Bajeli, Sapna, Akela, Ajit Kumar, Kumar, Ashwani
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874750/
https://www.ncbi.nlm.nih.gov/pubmed/29473841
http://dx.doi.org/10.3390/pathogens7010024
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author Iqbal, Iram Khan
Bajeli, Sapna
Akela, Ajit Kumar
Kumar, Ashwani
author_facet Iqbal, Iram Khan
Bajeli, Sapna
Akela, Ajit Kumar
Kumar, Ashwani
author_sort Iqbal, Iram Khan
collection PubMed
description 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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spelling pubmed-58747502018-04-02 Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery Iqbal, Iram Khan Bajeli, Sapna Akela, Ajit Kumar Kumar, Ashwani Pathogens Review 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. MDPI 2018-02-23 /pmc/articles/PMC5874750/ /pubmed/29473841 http://dx.doi.org/10.3390/pathogens7010024 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Iqbal, Iram Khan
Bajeli, Sapna
Akela, Ajit Kumar
Kumar, Ashwani
Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery
title Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery
title_full Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery
title_fullStr Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery
title_full_unstemmed Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery
title_short Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery
title_sort bioenergetics of mycobacterium: an emerging landscape for drug discovery
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874750/
https://www.ncbi.nlm.nih.gov/pubmed/29473841
http://dx.doi.org/10.3390/pathogens7010024
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