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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Pathway-selective sensitization of mycobacterium tuberculosis for target-based whole-cell screening
Chemistry and Biology, Volume 19, No. 7, Year 2012
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Description
Whole-cell screening of Mycobacterium tuberculosis (Mtb) remains a mainstay of drug discovery, but subsequent target elucidation often proves difficult. Conditional mutants that underexpress essential genes have been used to identify compounds with known mechanism of action by target-based whole-cell screening (TB-WCS). Here, the feasibility of TB-WCS in Mtb was assessed by generating mutants that conditionally express pantothenate synthetase (panC), diaminopimelate decarboxylase (lysA), and isocitrate lyase (icl1). The essentiality of panC and lysA, and conditional essentiality of icl1 for growth on fatty acids, was confirmed. Depletion of PanC and Icl1 rendered mutants hypersensitive to target-specific inhibitors. Stable reporter strains were generated for use in high-throughput screening, and their utility was demonstrated by identifying compounds that display greater potency against a PanC-depleted strain. These findings illustrate the power of TB-WCS as a tool for tuberculosis drug discovery. © 2012 Elsevier Ltd All rights reserved.
Authors & Co-Authors
Abrahams, Garth
South Africa, Johannesburg
University of the Witwatersrand
South Africa, Cape Town
University of Cape Town
Kumar, Anuradha
United States, Seattle
Seattle Biomedical Research Institute
Savvi, Suzana
South Africa, Johannesburg
University of the Witwatersrand
Hung, Alvin W.
United Kingdom, Cambridge
University of Cambridge
Wen, Shijun
United Kingdom, Cambridge
University of Cambridge
Abell, Chris
United Kingdom, Cambridge
University of Cambridge
Barry, Clifton Earl
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Sherman, David R.
United States, Seattle
Seattle Biomedical Research Institute
Boshoff, Helena Ingrid M.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Mizrahi, Valerie
South Africa, Johannesburg
University of the Witwatersrand
South Africa, Cape Town
University of Cape Town
Statistics
Citations: 119
Authors: 10
Affiliations: 5
Identifiers
Doi:
10.1016/j.chembiol.2012.05.020
ISSN:
10745521
Research Areas
Infectious Diseases