QcrB in Mycobacterium tuberculosis: The new drug target of antitubercular agents

Abstract

Drug‐resistance in mycobacterial infections is a major global health problem that leads to high mortality and socioeconomic pressure in developing countries around the world. From finding new targets to discovering novel chemical scaffolds, there is an urgent need for the development of better approaches for the cure of tuberculosis. Recently, energy metabolism in mycobacteria, particularly the oxidative phosphorylation pathway of cellular respiration, has emerged as a novel target pathway in drug discovery. New classes of antibacterials which target oxidative phosphorylation pathway either by interacting with a protein or any step in the pathway of oxidative phosphorylation can combat dormant mycobacterial infections leading to shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one such recently discovered target of the newly approved antitubercular drug bedaquiline. Cytochrome bcc is another new target of the antitubercular drug candidate Q203, currently in phase II clinical trial. Research suggests that b subunit of cytochrome bcc, QcrB, is the target of Q203. The review article describes the structure, function, and importance of targeting QcrB throwing light on all chemical classes of QcrB inhibitors discovered to date. An understanding of the structure and function of validated targets and their inhibitors would enable the development of new chemical entities.

Tuberculosis Drug Discovery: Challenges and New Horizons

“…Schematic representation of the oxidative phosphorylation pathway of Mtb , based on the description given by several authors − and modified from Bahuguna et al (Reproduced with permission from ref . Copyright 2021 John Wiley and Sons.…”

“…The QcrB subunit of cytochrome bcc (complex III) has been reported as the target of several small molecules with favorable anti-TB activity, including the drug candidate Q203 ( 23 ) in phase II clinical trials. ,,,, The morpholino-thiophene amide 96 (Figure ), derived from an Eli Lilly HTS hit ( 95 ) (Figure ), was revealed by Cleghorn et al to be a potent cytochrome bcc inhibitor at QcrB . Compound 96 displayed an MIC 90 value of 0.24 μM against Mtb H37Rv and modest cytotoxicity toward VERO cells (CC 50 39 μM).…”

Comparative Analysis on Proteomics Profiles of Intracellular and Extracellular M.tb and BCG From Infected Human Macrophages

“…Especially a series of oxidative phosphorylation pathway–related genes such as QcrA, QcrB, NuoL, NuoN, and CtaC that are closely related to energy metabolism were included. QcrA and QcrB are subunits of cytochrome-c complex, which is one of the transport electrons from the respiratory electron transport chain ( Bahuguna et al, 2021 ). To establish an infection in the cells after invasion under the environment of phagosomes with low pH and oxygen and starvation, M.tb in and BCG in have to reduce their energy consumption and put themselves in a kind of dormant state.…”

Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

“…Comparison to homologous terminal oxidases in Escherichia coli suggests that cytochrome bcc - aa 3 represents an energy-efficient terminal oxidase with low affinity for oxygen, whereas cytochrome bd is less energy-efficient but shows higher oxygen affinity and lower sensitivity to inhibitors such as nitric oxide and cyanide [ 9 , 10 , 11 , 12 ]. Targeting these terminal oxidases currently is regarded as a viable therapeutic strategy and has attracted strong attention in the TB drug discovery field [ 10 , 11 , 12 , 13 , 14 ].…”