Insights into the mechanism, structure and potential as drug target of the mycobacterial bd-type terminal oxidase

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis, possesses two terminal oxidases, the cytochrome bcc:aa3 (cyt-bcc:aa3) and the cytochrome bd (cyt-bd). While the cyt-bcc:aa3 is the target of the drug candidate Q203, the cyt-bd remains poorly understood. This work aimed to study the structure and function of the mycobacterial cyt-bd. Site-directed mutagenesis was used to identify unique functionally important regions of the cyt-bd. Attempts to purify the cyt-bd to resolve its structure were made. However, the complex could not be obtained in its intact form despite multiple attempts and optimizations. The involvement of the cyt-bd in the synergy between Q203 and clofazimine, an antitubercular drug, was evaluated, leading to a better understanding of the complex modes of action of clofazimine. In conclusion, the work presented in this thesis contributes to knowledge about the mycobacterial cyt-bd, from its structural features to its role in modulating potency of drugs, such as clofazimine.