Structure of mycobacterial cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates

Abstract

Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome bcc complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome bcc complex from these pathogenic mycobacteria. Here, we report the structures of M. tuberculosis cytochrome bcc alone (2.68 [A] resolution) and in complex with clinical drug candidates Q203 (2.67 [A] resolution) and TB47 (2.93 [A] resolution) determined by single-particle cryo-electron microscopy. M. tuberculosis cytochrome bcc forms a dimeric assembly with endogenous menaquinone/menaquinol bound at the quinone/quinol binding pockets. Q203 and TB47 are bound to the quinol-binding site. Hydrogen bonds are formed between the inhibitor and the side chains of QcrBThr313 and QcrBGlu314, residues that are conserved across pathogenic mycobacteria. These high-resolution structures provide a basis for the design of new mycobacterial cytochrome bcc inhibitors that could be developed into broad spectrum drugs to treat mycobacterial infections.