Tuberculosis (TB) is the leading cause of death due to an infectious agent worldwide. The enormous mortality rates associated with this disease are made worse by the emergence of multi-drug resistant bacteria. Thus, new drugs to treat TB are urgently needed. Unfortunately, few new drugs and drug targets have been validated against Mycobacterium tuberculosis (Mtb) despite considerable advances in our understanding of the biochemistry and metabolism of this bacterium. It has become apparent that not all essential metabolic processes represent good drug targets in bacteria. Fortunately, years of drug development efforts have revealed a number of bacterial processes that do appear to contain good targets for antibacterials. These processes include cell wall biosynthesis and cellular respiration. We propose to discover and develop inhibitors that target these druggable processes. To this end, we have developed screens that broadly detect cell wall biosynthesis and respiration inhibitors in Mtb. We have also demonstrated that our screens efficiently identify promising drug leads that are active against Mtb and are specific to these pathways. In our existing CETR, we identified DG167, a compound that inhibited KasA which is an essential enzyme involved in mycolic acid biosynthesis. DG167 has cidal activity against Mtb and it also eliminates persisters in vitro when used in combination with the first line anti- TB drug isoniazid. A CETR screen for respiration inhibitors also successfully identified DG70 and DG77. DG70 inhibited menaquinone biosynthesis, an essential component of cellular respiration in Mtb. DG70 has sterilizing synergy with several key first and second line TB drugs and it has potent activity against persistent forms of Mtb. Finally DG77 was confirmed to also inhibit respiration in Mtb, with the advantage that it had a very high genetic barrier to resistance and strong sterilizing activity in persistent cultures. DG167 has been successfully developed into a highly promising lead with greatly improved PK and activity in an acute mouse model of TB infection. Similarly, DG70 and DG77 have been improved to yield improved ADME as well as in vivo mouse efficacy. Here, we propose to further develop these promising cell wall and respiratory leads into optimized drug leads as pre- clinical candidates. We will also fully characterize existing and ongoing hits from our screens, and optimize the most promising of these into additional leads through our pipeline. Our three specific aims are: 1) Hit to lead and lead optimization of our DG167 analogs that target cell wall biosynthesis in Mtb. 2) Explore and optimize the anti- tubercular drug properties of our DG70 and DG77 compound series that inhibit respiration in Mtb. 3) Evaluate and develop our novel compounds that inhibit cell wall biosynthesis and respiration in Mtb, discovered through our PiniBAC, Pcyd and Pnark2 screens. Together, these three aims will discover, characterize and optimize a variety of compounds with novel targets that inhibit critical pathways in Mtb and greatly advance and accelerate the currently thin pre-clinical pipeline of anti-tuberculars with novel chemical series and new mechanisms of action.
This proposal will develop new therapies that will help to cure even the most drug resistant forms of tuberculosis. It will also have the potential to reduce the length of time need to treat tuberculosis and stop new resistance from happening. If achieved, our new therapy would be an important step towards the global eradication of tuberculosis.
