Cytochrome bd as survival factor in mycobacteria

Targeting respiration and ATP synthesis has received strong interest as a new strategy for combating drug-resistant Mycobacterium tuberculosis [1,2]. Mycobacteria employ a respiratory chain terminating with two branches. One of the branches includes a cytochrome bc1 complex and an aa3-type cytochrome c oxidase while the other branch terminates with a cytochrome bd-type quinol oxidase. We have shown that genetic inactivation of cytochrome bd, but not of cytochrome bc1, enhances the susceptibility of Mycobacterium smegmatis to hydrogen peroxide and antibiotic-induced stress [3]. The type-II NADH dehydrogenase effector clofazimine and the ATP synthase inhibitor bedaquiline were bacteriostatic against wild-type M. smegmatis, but strongly bactericidal against a cytochrome bd knock-out mutant [3,4]. These results identify cytochrome bd as a key survival factor in mycobacteria. The quinone-analog aurachin D inhibited mycobacterial cytochrome bd at sub-micromolar concentrations. Progress towards the characterization of cytochrome bd and its inhibitors will be discussed. Targeting the cytochrome bd respiratory branch appears to be a promising strategy that may enhance the bactericidal activity of existing tuberculosis drugs.