OVERALL APPROACH

TB Structural Genomic Consortium (TBSGC) target selection approach has always been based on a combination of genetic, structural, and biochemical approaches to understand the physiology of Mtb. At the same time, we leverage this knowledge to develop novel and tractable lead molecules using structure-guided drug discovery. Our unique approach uses genetics and genomics to identify essential and druggable target proteins that upon depletion make Mtb more susceptible to other known or new antituberculars. We then identify tractable small molecule inhibitors of these targets, optimize these inhibitors via a structure-guided approach, and use these valuable tools to probe Mtb physiology. This information together with the target structures, and inhibitor complexes becomes a very desirable starting point for drug development programs usually with our pharmaceutical partners, as shown below

The goals of this program will be to:

1) investigate fundamental biological mechanisms that determine drug synergy in Mtb,

2) define the structural relationship between novel targets and chemical inhibitors with the potential to be developed into combination therapeutics,

3) incorporate drug:drug interaction synergy into the early stages of drug discovery,

4) determine structures of membrane proteins involved in drug mode of action, and

5) to discover early-stage chemical inhibitors that are synergistic with existing TB therapeutics and new therapeutics in development.

The aspirational goal of the P01 is to reorient TB drug development toward targets and compounds that are likely to produce more effective combination regimens