Oxidative phosphorylation as a target space for tuberculosis: success, caution, and future directions
Cook, Gregory M.
Crick, Dean C.
Fontes, Fabio L.
Date of Issue2017
Lee Kong Chian School of Medicine (LKCMedicine)
The emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, have inspired scientists to seek out new targets for drug development. The Mycobacterium tuberculosis complex is a group of obligately aerobic bacteria that have specialized for inhabiting a wide range of intracellular and extracellular environments. Two fundamental features in this adaptation are the flexible utilization of energy sources and continued metabolism in the absence of growth. M. tuberculosis is an obligately aerobic heterotroph that depends on oxidative phosphorylation for growth and survival. However, several studies are redefining the metabolic breadth of the genus. Alternative electron donors and acceptors may provide the maintenance energy for the pathogen to maintain viability in hypoxic, nonreplicating states relevant to latent infection. This hidden metabolic flexibility may ultimately decrease the efficacy of drugs targeted against primary dehydrogenases and terminal oxidases. However, it may also open up opportunities to develop novel antimycobacterials targeting persister cells. In this review, we discuss the progress in understanding the role of energetic targets in mycobacterial physiology and pathogenesis and the opportunities for drug discovery.
© 2017 American Society for Microbiology. This paper was published in Microbiology Spectrum and is made available as an electronic reprint (preprint) with permission of American Society for Microbiology. The published version is available at: [http://dx.doi.org/10.1128/microbiolspec.TBTB2-0014-2016]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.