TC112

Whole-cell assays for the identification and classification of Mtb growth inhibitors

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Principal Investigator (PI)

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Project location

the sponsor

Home Institution

Dr. Schnappinger´s laboratory at Weill Cornell Medical College

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foundation funding

Foundation funding

The Foundation is providing £135,250.000 in support.

Open Labs Fellow/s

Dr. Shipra Grover

Project Participant

Shipra Grover

GSK’s contribution

GSK provides 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.

Publications 1

ACS infectious diseases, 7(1)

Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis

Grover, S., Engelhart, C. A., Pérez-Herrán, E., Li, W., Abrahams, K. A., Papavinasasundaram, K., Bean, J. M., Sassetti, C. M., Mendoza-Losana, A., Besra, G. S., Jackson, M., & Schnappinger, D.

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