Abstract
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 antibacterial 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antitubercular Agents / pharmacology*
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Antitubercular Agents / therapeutic use
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Bacterial Proteins / metabolism
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Carboxy-Lyases / antagonists & inhibitors*
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Carboxy-Lyases / genetics
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Carboxy-Lyases / metabolism
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Drug Resistance, Bacterial / genetics
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Endopeptidase Clp / metabolism
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Heat-Shock Proteins / metabolism
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Humans
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Microbial Sensitivity Tests
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Mutation
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / enzymology
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Mycobacterium tuberculosis / genetics
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Proteolysis / drug effects*
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Pyrazinamide / analogs & derivatives*
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Pyrazinamide / pharmacology
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Pyrazinamide / therapeutic use
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Tuberculosis / drug therapy
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Tuberculosis / microbiology
Substances
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Antitubercular Agents
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Bacterial Proteins
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ClpC1 protein, Mycobacterium tuberculosis
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Heat-Shock Proteins
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Pyrazinamide
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pyrazinoic acid
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Endopeptidase Clp
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Carboxy-Lyases
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aspartate 4-decarboxylase