Structure of <i>Mycobacterium tuberculosis</i> cytochrome <i>bcc</i> in complex with Q203 and TB47, two anti-TB drug candidates.

Abstract

Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome <i>bcc</i> complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome <i>bcc</i> complex from these pathogenic mycobacteria. Here, we report the structures of <i>Mycobacterium tuberculosis</i> cytochrome <i>bcc</i> alone (2.68 Å resolution) and in complex with clinical drug candidates Q203 (2.67 Å resolution) and TB47 (2.93 Å resolution) determined by single-particle cryo-electron microscopy. <i>M. tuberculosis</i> cytochrome <i>bcc</i> forms a dimeric assembly with endogenous menaquinone/menaquinol bound at the quinone/quinol-binding pockets. We observe Q203 and TB47 bound at the quinol-binding site and stabilized by hydrogen bonds with the side chains of _QcrBThr³¹³ and _QcrBGlu³¹⁴, residues that are conserved across pathogenic mycobacteria. These high-resolution images provide a basis for the design of new mycobacterial cytochrome <i>bcc</i> inhibitors that could be developed into broad-spectrum drugs to treat mycobacterial infections.