ATP Synthesis Inhibitors

The TB drug bedaquiline targets the ATP synthase enzyme of the TB mycobacteria. ATP synthase is an essential enzyme in the process by which M.tb generates energy in the form of ATP. This project identified a number of inhibitors of this ATP synethesis. This was achieved through a membrane-based screen that has the potential to identify inhibitors of the various targets that constitute the ATP synthesis pathway including Ndh-2, various cytochromes, and the target for bedaquiline, ATP synthase. One chemical series was identified from an HTS of GNF compounds which demonstrated the target inhibition and an MIC against M. tuberculosis. New analogues were synthesized and tested in anti-Mtb activity, in vitro ADME, mouse PK, and in vivo efficacy studies. To date one analogue has demonstrated an in vivo efficacy.