Abstract
The bacterium Mycobacterium tuberculosis is responsible for the highest number of deaths
caused by a single infectious agent. With almost a third of the global population infected with
M .tuberculosis it is imperative that new effective treatment options are identified. This need
for new inhibitors has been exacerbated by the rapid rise of drug resistance in M. tuberculosis
including resistance to drugs only recently approved for use. One area of study that has shown
great promise for the identification of new treatment options has been the electron transport
chain of M. tuberculosis. In particular the cytochrome bd oxidase, of which the structure has
recently been resolved, has shown promise as a candidate drug target. Dual inhibition of the
terminal oxidases, cytochrome bcc:aa3 super-complex and cytochrome bd oxidase has been
shown to be lethal to M. tuberculosis and inhibition of the cytochrome bd oxidase has been
shown to synergise with other electron transport chain inhibitors. In this study compounds
identified by in-silico screening were screened in vitro for the ability to effectively and
selectively inhibit the M. tuberculosis cytochrome bd oxidase. The methods developed allowed
for the identification of several lead compounds able to inhibit the M. tuberculosis cytochrome
bd oxidase and determination of their potency through IC50 assays. In addition, the study
investigated the impact of substitution mutations of key residues of M. tuberculosis cytochrome
bd oxidase and identified differing impacts.