Cytochrome bc1:aa3 oxidase supercomplex (bc1:aa3)

The Cytochrome bc1:aa3 oxidase supercomplex is a critical component of the Mycobacterium tuberculosis respiratory chain, responsible for transferring electrons from menaquinol to oxygen and generating the proton motive force required for ATP synthesis (Current Molecular Pharmacology, 2022; PNAS, 2017). It consists of two main parts: the cytochrome bc1 complex (menaquinone:cytochrome c reductase) and the cytochrome aa3 oxidase (cytochrome c oxidase), which form an obligate supercomplex in mycobacteria (Nature Medicine, 2013; eLife, 2021). This supercomplex is a validated therapeutic target, with the QcrB subunit of the bc1 complex being the primary binding site for several novel antitubercular agents, most notably Telacebec (Q203) (Nature Medicine, 2013; Expert Opinion on Investigational Drugs, 2022). Inhibition of this target leads to a rapid collapse of intracellular ATP levels, although the presence of an alternative terminal oxidase, cytochrome bd, can provide respiratory flexibility and limit the bactericidal efficacy of bc1:aa3 inhibitors (PNAS, 2017; EMBO Molecular Medicine, 2020). Consequently, current research explores combining bc1:aa3 inhibitors with other agents to overcome this redundancy and achieve more effective sterilization of M. tuberculosis infections, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains (Antimicrobial Agents and Chemotherapy, 2022). The target's high specificity for mycobacterial enzymes over human mitochondrial homologs minimizes host toxicity, making it a promising focus for the development of shorter, safer treatment regimens for tuberculosis and other mycobacterial diseases like Buruli ulcer and leprosy (NEJM, 2020; Qurient, 2021).

Other names

Cytochrome bc1 complexCytochrome aa3 oxidaseQcrBCytochrome bcc:aa3 supercomplexMenaquinone:cytochrome c reductaseUbiquinol-cytochrome c reductase

Inhibition of the QcrB subunit (cytochrome b) of the cytochrome bc1 complex, which disrupts the electron transport chain and leads to a rapid depletion of intracellular ATP levels.