Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria

Abstract

Mycobacteria inhabit a wide range of intracellular and extracellular environments. Many of these environments are highly dynamic and therefore mycobacteria are faced with the constant challenge of redirecting their metabolic activity to be commensurate with either replicative growth or a non-replicative quiescence. A fundamental feature in this adaptation is the ability of mycobacteria to respire, regenerate reducing equivalents and generate ATP via oxidative phosphorylation. Mycobacteria harbor multiple primary dehydrogenases to fuel the electron transport chain and two terminal respiratory oxidases, an aa3-type cytochrome c oxidase and cytochrome bd-type menaquinol oxidase, are present for dioxygen reduction coupled to the generation of a protonmotive force. Hypoxia leads to the downregulation of key respiratory complexes, but the molecular mechanisms regulating this expression are unknown. Despite being obligate aerobes, mycobacteria have the ability to metabolize in the absence of oxygen and a number of reductases are present to facilitate the turnover of reducing equivalents under these conditions (e.g. nitrate reductase, succinate dehydrogenase/fumarate reductase). Hydrogenases and ferredoxins are also present in the genomes of mycobacteria suggesting the ability of these bacteria to adapt to an anaerobic-type of metabolism in the absence of oxygen. ATP synthesis by the membrane-bound F1FO-ATP synthase is essential for growing and non-growing mycobacteria and the enzyme is able to function over a wide range of protonmotive force values (aerobic to hypoxic). The discovery of lead compounds that target respiration and oxidative phosphorylation in Mycobacterium tuberculosis highlights the importance of this area for the generation of new front line drugs to combat tuberculosis.

Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection

“…Discussion M. tuberculosis is an obligate aerobe that can survive, but not replicate, under hypoxic conditions. The reasons for the strict dependence on oxygen for growth are poorly understood but illustrate the prominence of aerobic respiration and the terminal respiratory oxidases for the biology of this bacterium (11). In the past 10 y the discovery of drugs active against enzymes of the mycobacterial oxidative phosphorylation pathway, namely, inhibitors of ATP-synthase (BDQ) and Cyt-bc 1 :aa 3 (imidazopyridine amides), have confirmed this vulnerability.…”

“…Dissipation of the pmf leads to a rapid loss of cell viability and cell death. Therefore, drugs targeting enzymes involved in pmf generation are predicted to reduce time of therapy by killing phenotypic drug-resistant bacterial subpopulations (11).…”

Copper Oxidation State and Mycobacterial Infection

“…This Cu 2+ could, at least in principle, be re-reduced by non-enzymatic copper reduction via menaquinones in the membrane of Mycobacteria, restoring the more toxic Cu + pool. However, this reaction is unlikely to occur because Mycobacteria harbor two terminal oxidases, a cytochrome aa s oxidase and a cytochrome bd oxidase [35], which would effectively compete with non-enzymatic copper reduction.…”

Acetate Dissimilation and Assimilation in Mycobacterium tuberculosis Depend on Carbon Availability

“…Indeed, genes involved in classical fermentative pathways are lacking in the genome of M. tuberculosis (4), and products of fermentation such as lactate and formate have not been reported for M. tuberculosis so far. Furthermore, the ATP synthase is essential in mycobacteria, whereas in bacteria that are capable of fermentation, respiratory ATP production is often dispensable (29). However, besides during fermentation, E. coli also produces acetate in the presence of large amounts of glycolytic substrates.…”