Targeting Energy Metabolism in Mycobacterium tuberculosis

Mycobacterium tuberculosis relies on a finely tuned energy metabolism to sustain growth, virulence and persistence within the host. Central to this process is oxidative phosphorylation, whereby electrons flow through a branched electron transport chain (ETC) to generate a proton motive force that drives ATP synthesis. This pathway is essential not only for actively dividing bacilli but also for dormant, non-replicating subpopulations that underlie latent infections. Recent advances have revealed multiple enzyme complexes within the ETC and associated respiratory components as druggable targets. Inhibitors of ATP synthase, cytochrome bc1–aa3 oxidase and type-2 NADH dehydrogenase have demonstrated potent bactericidal activity, even against drug-resistant strains. The remarkable plasticity of the mycobacterial respiratory chain enables rerouting of electrons under chemical stress, but also exposes vulnerabilities that can be exploited through combination therapies. By disrupting energy homeostasis, new regimens promise to shorten treatment duration, overcome persistence mechanisms and tackle multidrug-resistant tuberculosis on a global scale.

Research from Nature Portfolio

Studies have delineated the flexibility of the M. tuberculosis ETC in response to single-agent inhibition. When key respiratory complexes are blocked, the bacterium reroutes electron flow through alternative terminal oxidases to maintain ATP levels, a process that simultaneously increases reactive oxygen species production and sensitises the pathogen to co-administered compounds. Exploiting this effect, combination regimens targeting multiple branches of the ETC produce synergistic killing in vitro and in macrophage infection models. Other work has demonstrated the pathogen’s intrinsic plasticity by showing that deletion of presumed essential components, such as the cytochrome bc1–aa3 oxidase or type-2 NADH dehydrogenase, yields only partial attenuation in animal models, underscoring the need to target multiple respiratory nodes simultaneously. In parallel, repurposing efforts have identified an approved proton-pump inhibitor as a prodrug that, upon intracellular activation, selectively inhibits the mycobacterial cytochrome bc1 complex without affecting human targets. Together, these findings highlight a strategy of simultaneously undermining energy conservation and elevating oxidative stress to potentiate bactericidal efficacy.

Targeting Energy Metabolism in Mycobacterium tuberculosis publication trend

The graph below shows the total number of articles in targeting energy metabolism in mycobacterium tuberculosis across all publications each year (not limited to Nature Index journals).

Technical terms

Oxidative phosphorylation: A metabolic process in which electrons are transferred through the ETC to generate a proton gradient used by ATP synthase to produce ATP.

Electron transport chain (ETC): A series of membrane-bound proteins and mobile carriers that shuttle electrons, culminating in oxygen reduction and proton translocation.

ATP synthase: A membrane enzyme complex that converts the proton motive force into adenosine triphosphate (ATP), the cell’s primary energy currency.

Terminal oxidase: An enzyme complex at the end of the ETC that reduces oxygen to water, with variations (e.g., cytochrome bc1–aa3, cytochrome bd) offering respiratory flexibility.

Non-replicating mycobacteria: Dormant bacilli with low metabolic activity that can persist in host tissues and are tolerant to many conventional drugs.

References

1. Inhibiting respiration as a novel antibiotic strategy. Current Opinion in Microbiology (2023).
2. Assessment of the Efficacy of the Antihistamine Drug Rupatadine Used Alone or in Combination against Mycobacteria. Pharmaceutics (2024).
3. Targeting Energy Metabolism in Mycobacterium tuberculosis, a New Paradigm in Antimycobacterial Drug Discovery. mBio (2017).
4. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nature Communications (2016).
5. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nature Communications (2015).
6. Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development. Nature Communications (2019).