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Structure of Mycobacterium tuberculosis 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 Mycobacterium tuberculosis cytochrome bcc 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. M. tuberculosis cytochrome bcc 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 bcc inhibitors that could be developed into broad-spectrum drugs to treat mycobacterial infections.

SUBMITTER: Zhou S 

PROVIDER: S-EPMC8616580 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Zhou Shan S   Wang Weiwei W   Zhou Xiaoting X   Zhang Yuying Y   Lai Yuezheng Y   Tang Yanting Y   Xu Jinxu J   Li Dongmei D   Lin Jianping J   Yang Xiaolin X   Ran Ting T   Chen Hongming H   Guddat Luke W LW   Wang Quan Q   Gao Yan Y   Rao Zihe Z   Gong Hongri H  

eLife 20211125


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 TB4  ...[more]

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