Oxidative phosphorylation as a target space for tuberculosis: Success, caution, and future directions

The genus Mycobacterium comprises a group of obligately aerobic bacteria that have adapted to inhabit a wide range of intracellular and extracellular environments. Fundamental to this adaptation is the ability to respire and generate energy from variable sources and to sustain metabolism in the absence of growth. The pioneering work of Brodie and colleagues on Mycobacterium phlei established much of the primary information on the electron transport chain and oxidative phosphorylation system in mycobacteria (reviewed in 1). Mycobacteria can only generate sufficient energy for growth by coupling the oxidation of electron donors derived from organic carbon catabolism (e.g., NADH, succinate, malate) to the reduction of O₂ as a terminal electron acceptor. Mycobacterial genome sequencing revealed that branched pathways exist in mycobacterial species for electron transfer from many low-potential reductants, via quinol, to oxygen (Fig. 1).