Fundamental and applied investigations into mycobacterial bioenergetics

Abstract

From the war on drug resistance, through cancer biology, even to agricultural and environmental protection; there is a huge demand for rapid and effective solutions to infections and diseases. The development of small molecule inhibitors was once an accepted “one-size fits all” approach to these varied problems, but persistence and resistance threaten to return society to a pre-antibiotic era. Nowhere is this more apparent than the treatment and management of Mycobacterium tuberculosis (TB) infections. The extremely long therapy timeframes needed to clear persistent cells, followed by the advent of extensively and totally drug resistant infections, indicate a failure in the development and efficacy of antibiotics. Only 5 out of approximately 200 conserved essential bacterial targets are utilized, which are flawed by their bias toward growing cells. Recently, a medical revolution was instigated by the FDA approval of the antitubercular bedaquiline (BDQ), which is more effective than its rival therapeutics at clearing persister TB cells. This drug targets the F1Fo-ATP synthase and so classifies cellular energy generation as the 6th antibiotic target space. At the time of writing, this has been a medically valid target space for less than 5 years. There is understandably a huge paucity of information on function, scope and safety of both inhibitors and targets within this target-space. A multidisciplinary approach, encompassing chemical biology, bioinformatics, biochemistry and physiology, is used to understand both this new drug and a new target in TB bioenergetics; combining both fundamental and applied approaches in this space. Both strands of study reveal new ways in which the generation of the proton motive force (PMF) in persistent cells is both applicable to therapeutics and distinct from model systems. A uniquely strict regulation of PMF generation is argued to have tailored the physiology of the Mycobacterium genus for survival in hostile environments, in a way that is easily abusable by the avid drug-developer. Integration of this work with other recent studies is used to make an argument that all antibiotics kill bacteria by disrupting the PMF, extending the applicability of this target-space significantly. As a high profile and newly emerging field of research, with minimal room for error, strategies to improve our understanding of the efficacy and safety of these new antimicrobials are discussed.