Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions

Abstract

Chapter summary The emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, has 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 (OXPHOS) 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.

Anaerobic nitrate respiration in the aerobe Streptomyces coelicolor A3(2): helping maintain a proton gradient during dormancy

“…The capacity to synthesize Nar enzymes, and thus perform nitrate reduction, has been identified in only certain species of the streptomycetes; however, amongst the aerobic actinobacteria, nitrate reduction is not exclusive to streptomycetes. Nar enzymes have been identified and characterized in Corynebacterium and Mycobacterium species (Bott and Niebisch, ; Cook et al ., ). As with S. coelicolor , Nar activity in these other genera is insufficient to support growth and always correlates with O 2 limitation.…”

“…We know essentially nothing about the biochemical processes that underlie this presumed down‐shift in metabolism, but such processes are highly relevant to the numerous microorganisms living in the oligotrophic deep biosphere (Hoehler and Jørgensen, ). Understanding the bioenergetic processes controlling non‐growth and dormancy, as well as the metabolic ‘escape’ from these states, will be important in revealing how microbial cells can maintain a membrane potential for tens, hundreds or even thousands of years (Cano and Borucki, ) on an highly restricted ‘diet.’ This area of research also has relevance to the study of persistence in pathogens, how bacteria combat antibiotic resistance and even aging processes (Lewis, ; Cook et al ., ).…”

Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence

“…SQ109 (Sequella) is thought to disrupt the biosynthesis of the electron carrier menaquinone and the pmf through uncoupling activity (4). The pmf generated by the ETC is an essential element for the survival of any organism under both aerobic and hypoxic growth conditions, which makes this system attractive for drug development (5).…”

Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity

“…[17] Furthermore, due to the druggability of targets in this pathway, as evidenced here and elsewhere, it remains an opportunity for anti-TB drug discovery. [3,18] By using a pathway-based screen in mycobacterial membranes, we identified inhibitors that block oxidative phosphorylation and prevent Mtb growth through disruption of Ndh-2 activity.…”