Mycobacterial Gyrase Inhibitors

Chemical Class:
Novel structural class
This project aims to develop compounds that kill M.tb by inhibiting DNA gyrase. DNA gyrase, an important enzyme found in all bacteria, is a proven target for antibacterial chemotherapy. Fluoroquinolones, a class of synthetic antimicrobial agents that have demonstrated activity in TB treatment, kill bacteria by inhibiting bacterial DNA gyrase and topoisomerase IV in most bacterial species. M.tb DNA gyrase is thus a validated target for antitubercular drug discovery; its inhibition results in high mycobactericidal activity against both actively replicating and non-replicating, persistent mycobacteria, which might be important for shortening the duration of TB therapy. A novel inhibitor of M.tb DNA gyrase would also be effective against multi-drug resistant TB (MDR-TB), and will likely be effective against fluoroquinolone-resistant M.tb if it binds to a different site on that enzyme from that where fluoroquinolones bind. The efficacy of these compounds within this program has been demonstrated in both the acute and chronic mouse infection models and now data on their safety are being generated.