Mycobacterial Membrane Proteins QcrB and AtpE: Roles in Energetics, Antibiotic Targets, and Associated Mechanisms of Resistance.

Infections caused by mycobacteria are difficult to treat due to their inherent physiology, cellular structure, and intracellular lifestyle. Mycobacterium tuberculosis is a pathogen of global concern as it causes tuberculosis (TB) in humans, which requires 6-9 months of chemotherapy. The situation is further exacerbated in the case of infections caused by drug-resistant strains, which necessitate the prolonged use of agents associated with increased host toxicities. Great effort has been invested into the development of new agents for the treatment of drug-resistant infections, in addition to novel strategies to reduce treatment time. Energy production using oxidative phosphorylation is essential for the survival of M. tuberculosis, even under conditions of dormancy. Many compounds have been recently discovered that inhibit different aspects of energy metabolism in mycobacteria, some of which have been approved for human use or are currently undergoing development. The most successful examples include inhibitors of QcrB and AtpE, which are part of the cytochrome bc complex and FF-ATP synthase, respectively. In addition, many of the discovered inhibitors are active against drug-resistant strains of M. tuberculosis, inhibit nonreplicating cells, and also show potential for the treatment of other mycobacterial infections. In the current review, we focus on the discovery of mycobacterial QcrB and AtpE inhibitors, their modes of action, and the associated mechanisms of resistance observed to date.