Targeting Oxidative Phosphorylation for the Rational Development of Sterilising Drug Combination for Drug-resistant Tuberculosis

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), kills more people than any other bacterium. TB control is threatened by the continued spread of drug resistance; multi-drug and extensively drug resistant Mtb require longer, more costly, treatment with multiple drugs causing worse side effects and have a lower likelihood of treatment success. The urgent need for better treatment options for drug resistant Mtb has led the World Health Organization to prioritize development of not only new individual antitubercular agents, but also new drug regimens. Mtb is an obligate aerobe, requiring the use of its branched electron transport chain (ETC) for energy production via oxidative phosphorylation (OXPHOS). Even during hypoxic non-replicating persistence, Mtb uses its ETC to maintain its proton motive force (PMF). OXPHOS catalyzed by cyt-bd-, cyt-bcc-aa3 and F-ATP synthase lies at the heart of bacterial bioenergetics. Our team has unraveled • Nature’s paradigms for securing energy inside mycobacteria by identifying that three subunits of Mtb F-ATP synthase contribute to the suppression of OXPHOS and PMF-maintenance, • discovered novel targets inside these subunits. • Identified a new compound against the drug epitope of one Mtb F-ATP synthase subunit. • Unraveled that cyt-bd will be one cornerstone of a sterilizing drug regimen for multi-drug resistant tuberculosis. • Discovered the first cell-active small-molecules targeting the cyt-bd. The proposal describes a research program that will combine understanding and translation of oxidative phosphorylation operation by forming a network of experts, whose overall goals are: • To archive novel structural information about domains of Mtb F-ATP synthase and cyt-bd, which together with own developed compounds will pave the way to identify new leads. • To deliver a preclinical development candidate. • To develop diarylquinolines (BDQ) analogues with improved properties. • To archive synergistic efficacy of multi-drug combination.