Targeting the cytochrome oxidases for drug development in mycobacteria

Mycobacterium tuberculosis strictly depends on oxygen to multiply, and the terminal oxidases are a vital part of the oxidative phosphorylation pathway. The bacterium possesses two aerobic respiratory branches: a cytochrome bcc-aa₃ and a bacteria-specific cytochrome bd oxidase. The identification of small-molecule inhibitors of the cytochrome bcc-aa₃ under numerous experimental conditions reflects the essentiality of the pathway for the optimum growth of M. tuberculosis. Recent findings on the biology of the cytochrome bcc-aa₃ as well as the report of the first high-resolution structure of a mycobacterial cytochrome bcc-aa₃ complex will help in the characterization and further development of potent inhibitors. Although the aerobic cytochrome bd respiratory branch is not strictly essential for growth, the discovery of a strong synthetic lethal interaction with the cytochrome bcc-aa₃ placed the cytochrome bd oxidase under the spotlight as an attractive drug target for its synergistic role in potentiating the efficacy of cytochrome bcc-aa₃ inhibitors and other drugs targeting oxidative phosphorylation. In this review, we are discussing current knowledge about the two mycobacterial aerobic respiratory branches, their potential as drug targets, as well as potential drawbacks.