title: Targeting Energy Metabolism inMycobacterium tuberculosis, a New Paradigm in Antimycobacterial Drug Discovery.
abstract: Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New innovative approaches, from identification of new targets to discovery of novel chemical scaffolds, are urgently needed. Recently, energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, has emerged as an object of intense microbiological investigation and as a novel target pathway in drug discovery. New classes of antibacterials interfering with elements of the oxidative phosphorylation pathway are highly active in combating dormant or latent mycobacterial infections, with a promise of shortening tuberculosis chemotherapy. The regulatory approval of the ATP synthase inhibitor bedaquiline and the discovery of Q203, a candidate drug targeting the cytochromebc1complex, have highlighted the central importance of this new target pathway. In this review, we discuss key features and potential applications of inhibiting energy metabolism in our quest for discovering potent novel and sterilizing drug combinations for combating tuberculosis. We believe that the combination of drugs targeting elements of the oxidative phosphorylation pathway can lead to a completely new regimen for drug-susceptible and multidrug-resistant tuberculosis.
authors.affiliation: Department of Molecular Cell Biology, AIMMS, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands d.bald@vu.nl akoul@its.jnj.com.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bald
authors.affiliation: Infectious Diseases and Vaccines Therapeutic Area, Janssen Research & Development, Beerse, Belgium.
authors.forename: Cristina
authors.initials: C
authors.lastname: Villellas
authors.affiliation: Department of Molecular Cell Biology, AIMMS, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Infectious Diseases and Vaccines Therapeutic Area, Janssen Research & Development, Beerse, Belgium d.bald@vu.nl akoul@its.jnj.com.
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D055808:Drug Discovery / Q000639:trends*; D004734:Energy Metabolism / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects
chemical_list: D000995:Antitubercular Agents
keywords: Mycobacterium tuberculosis; antibiotics; energy metabolism; oxidative phosphorylation