Weill Cornell Medical College

Start : April 2014 | Status : Complete

The scientists: Dr. Shipra Grover is an experienced microbiologist who completed her doctoral studies in University of Birmingham (UK) under the supervision of Dr. Gurdyal Besra.  Shipra has focused her research on uncovering the mode of action of new antituberculars and the transcriptional regulation of genes involved in cell wall biosynthesis.

The sponsor: Dr. Schnappinger´s laboratory at Weill Cornell Medical College pioneered the development of regulated expression systems for mycobacteria  and showed how these systems can conditionally silence Mtb genes during mouse infections. The application of these novel technologies to drug discovery has allowed the (i) functional classification of Mtb growth inhibitors, and (ii) the application of novel target-biased whole cell screening anti-mycobacterial programs.

Foundation funding:  £135,250

GSK’s contribution: GSK is providing in-kind contributions including access to BSL3 facilities, HTS and microbiology expertise as well as full access to antimycobacterial compounds sets.

Project Description: Whole-cell screens (WCS) have recently been re-visited as an antibacterial drug discovery strategy. This change is due to the lack of success associated with biochemical target-based high throughput screens (HTS), where potent enzyme inhibitors poorly active  as antibacterials were identified. However, the ability to select for whole-cell activity during the HTS phase comes at the price of knowing little (if anything) about the mechanism(s) by which a novel compound inhibits bacterial growth. The use of regulated expression sytems can help overcome this shortcoming and identify the molecular target(s) of growth-inhibiting small molecules.
The mode of action elucidation of GSK antitubercular compound sets by means of the conditional mutants developed by Dirk Schnappinger´s group at Cornell will be the base of this new whole cell target-based project.