Cytochrome b subunit of the menaquinol-cytochrome c reductase (QcrB) (QcrB)

Mycobacterium tuberculosis QcrB is a vital transmembrane subunit of the cytochrome bc1:aa3 supercomplex, which functions as a menaquinol-cytochrome c oxidoreductase within the bacterial electron transport chain (UniProt: P9WIP9). It plays a central role in oxidative phosphorylation by facilitating electron transfer and contributing to the generation of the proton motive force necessary for ATP synthesis (Nature Medicine, 2013, 19(9):1157-60). As M. tuberculosis is an obligate aerobe that depends on this respiratory pathway for survival during both active infection and dormancy, QcrB is a validated therapeutic target for treating tuberculosis (Science Translational Medicine, 2018, 10(455)). Small molecules like Telacebec (Q203) target the menaquinol-binding Qo site of QcrB, leading to a rapid depletion of intracellular ATP and subsequent bacterial death (New England Journal of Medicine, 2020, 382:12). This target is especially significant for developing treatments against multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, as it offers a novel mechanism of action distinct from current first-line therapies (Antimicrobial Agents and Chemotherapy, 2019, 63(5)). Clinical development of QcrB inhibitors has demonstrated potent bactericidal activity and the potential to shorten treatment durations for tuberculosis patients (Lancet Infectious Diseases, 2021). Resistance to these inhibitors typically arises through specific point mutations in the qcrB gene, such as those affecting the Ala317 or Thr313 residues, which alter the drug-binding pocket (Nature Communications, 2015, 6:7695). Despite the risk of resistance, QcrB remains a cornerstone of next-generation antitubercular drug discovery due to its essentiality and lack of a human homolog (Journal of Medicinal Chemistry, 2019, 62(17):7618-7637).

Other names

Ubiquinol-cytochrome c reductase subunit bRv2195Cytochrome bMenaquinol-cytochrome c reductase subunit bCytochrome b subunit of the bc1 complex

Inhibition of the cytochrome bc1 complex by binding to the menaquinol-binding (Qo) site, disrupting the electron transport chain and depleting cellular ATP levels.