Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-15516-1
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Funding
- Singapore Ministry of Health's National Medical Research Council [NMRC/TCR/011-NUHS/2014, NMRC/CG/013/2013]
- Yong Loo Lin School of Medicine graduate scholarship
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [2R01AI10639805, P01AI095208]
- Bill and Melinda Gates Foundation [OPP1181211]
- National Research Foundation (NRF) Singapore [NRF-CRP18-2017-01]
- Bill and Melinda Gates Foundation [OPP1181211] Funding Source: Bill and Melinda Gates Foundation
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Pyrazinamide is a sterilizing first-line tuberculosis drug. Genetic, metabolomic and biophysical analyses previously demonstrated that pyrazinoic acid, the bioactive form of the prodrug pyrazinamide (PZA), interrupts biosynthesis of coenzyme A in Mycobacterium tuberculosis by binding to aspartate decarboxylase PanD. While most drugs act by inhibiting protein function upon target binding, we find here that pyrazinoic acid is only a weak enzyme inhibitor. We show that binding of pyrazinoic acid to PanD triggers degradation of the protein by the caseinolytic protease ClpC1-ClpP. Thus, the old tuberculosis drug pyrazinamide exerts anti-bacterial activity by acting as a target degrader, a mechanism of action that has recently emerged as a successful strategy in drug discovery across disease indications. Our findings provide the basis for the rational discovery of next generation PZA.
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