Energy metabolism and membrane energetics pathways in Mycobacterium tuberculosis

Energy metabolism and membrane energetics in Mycobacterium tuberculosis (Mtb) encompass the biochemical processes that generate adenosine triphosphate (ATP) and maintain the electrochemical gradient across the bacterial inner membrane (Cook et al., 2014, Nature Reviews Microbiology). These pathways are critical for Mtb survival across various physiological states, including active replication and dormancy within the host granuloma (Beste et al., 2009, Genome Biology). The respiratory chain of Mtb is highly flexible, utilizing multiple primary dehydrogenases and terminal oxidases to adapt to varying oxygen levels and carbon sources. Therapeutic targeting of these pathways has proven highly effective, as evidenced by the success of bedaquiline, which inhibits the F1F0-ATP synthase (Andries et al., 2005, Nature). Other emerging drugs like telacebec (Q203) target the QcrB subunit of the cytochrome bc1 complex, disrupting the electron transport chain (Pethe et al., 2013, Nature Medicine). Clofazimine, a long-standing anti-leprosy drug, has been shown to act as a prodrug that is reduced by NDH-2 to generate reactive oxygen species, further disrupting energetics (Yano et al., 2011, Journal of Biological Chemistry). Because these energetic processes are essential and distinct from human mitochondrial counterparts in specific structural details, they offer a high degree of selectivity for treating both drug-sensitive and multi-drug-resistant tuberculosis.

Other names

Mtb oxidative phosphorylationMtb respiratory chainMtb bioenergeticsMtb electron transport chain

Inhibition of the F1F0-ATP synthase, inhibition of the cytochrome bc1:aa3 oxidase complex (QcrB), and reduction of the menaquinone pool via NADH dehydrogenase inhibition.