12:00noon Monday 4th November
Room 208, 2nd floor,
Microbiology building,
720 Cumberland Street
Tuberculosis (TB) remains one of the leading worldwide causes of infectious disease mortality globally, with over one million annual deaths. The discovery of the imidazopyridine amide series (e.g. Q203), nanomolar inhibitors currently in clinical trials that inhibit mycobacterial respiration, has sparked interest in the targeting of terminal respiratory oxidases to treat drug-resistant TB disease. Mycobacteria have two terminal respiratory oxidases, a cytochrome bc1-aa3-type cytochrome c oxidase (qcrCAB operon – bc1 complex) and a cytochrome bd-type menaquinol oxidase (cydAB operon). The former is typically thought to have a lower affinity for oxygen than the latter, and this has typecast their proposed physiological roles. We report on the bioenergetic parameters of markerless cytochrome bd (cydAB) and bc1 (DqcrCAB) mutants of M. smegmatis and propose that the roles of each oxidase are more nuanced than their expected affinities for oxygen. We also report on the mode of action of TB47, a next-generation inhibitor that targets the bc1 complex.
