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, protein synthesis and DNA gyrase. In the case of Mtb, respiration also appears to be a promising druggable cellular process. We propose to discover and develop inhibitors that target these druggable processes. To this end, we have developed a screen that broadly detects cell wall biosynthesis inhibitors. We have also demonstrated that our screen efficiently identifies promising drug leads that are active against Mtb and are specific to this process. Our group has already characterized the activity and identified the novel target of a class of compounds (theophenes or TPs) that were first identified in our cell wall biosynthesis inhibitor screen. The TPs inhibit Pks13, an essential enzyme involved in mycolic acid biosynthesis. These compounds have cidal activity against Mtb and eliminate persisters in vitro when used in combination with the first line anti-TB drug isoniazid. Our screening/discovery approach can also be adapted to identify inhibitors that are specific to other druggable cellular processes. Here, we propose to develop the most promising cell wall inhibitors that we have discovered into optimized drug leads. We will also fully characterize the remaining hits from our screen. We will also expand our screening approach to uncover new inhibitors and novel targets in the druggable processes of protein synthesis, DNA gyrase and respiration. Our three specific aims are to: 1) Optimize the drug properties of our lead TP compounds. 2) Discover the targets of novel cell wall inhibitors identified by our cell wall screen, and study the metabolic consequences of target inhibition. 3) Identify new hit compounds that inhibit targets within pathways essential to protein synthesis, DNA gyrase, and respiration.
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