Mycobacterium tuberculosis targets involved in membrane energetics in acidic environments

Mycobacterium tuberculosis (Mtb) targets involved in membrane energetics in acidic environments represent a critical suite of proteins and complexes that allow the pathogen to survive within the hostile, acidic milieu of the host macrophage phagolysosome (pH 4.5–5.5) [1, 2]. This functional system primarily includes the F1F0-ATP synthase, the respiratory electron transport chain (ETC) components such as the cytochrome bc1-aa3 complex (QcrB) and cytochrome bd oxidase, and pH-regulatory proteins such as the acid-resistance protease MarP [3, 8]. These targets work coordinately to maintain the proton motive force (PMF), which is required for ATP synthesis and the active regulation of intrabacterial pH to prevent lethal cytoplasmic acidification [2, 11]. Drugs like Bedaquiline (targeting ATP synthase) and Telacebec (targeting QcrB) exploit the bacterium's increased reliance on these pathways under acid stress, leading to rapid ATP depletion and loss of viability [3, 12]. Additionally, the first-line drug Pyrazinamide is thought to act by disrupting membrane potential and energetics specifically in acidic environments [13]. Because these targets are vital for both actively replicating and non-replicating persistent Mtb populations, they are central to modern efforts to shorten tuberculosis treatment and combat multidrug-resistant strains [7, 10].

Other names

Mycobacterium tuberculosis oxidative phosphorylation pathwayMycobacterium tuberculosis respiratory chainMycobacterium tuberculosis pH homeostasis machineryMycobacterium tuberculosis bioenergetics

Inhibition of F1F0-ATP synthase, inhibition of cytochrome bc1-aa3 complex, disruption of proton motive force, and inhibition of acid-resistance proteases.