Pyrazinamide triggers degradation of its target aspartate decarboxylase

Pooja Gopal, Jickky Palmae Sarathy, Michelle Yee, Priya Ragunathan, Joon Shin, Shashi Bhushan, Junhao Zhu, Tatos Akopian, Olga Kandror, Teck Kwang Lim, Martin Gengenbacher, Qingsong Lin, Eric J. Rubin, Gerhard Grüber and Thomas Dick ()
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Pooja Gopal: National University of Singapore
Jickky Palmae Sarathy: National University of Singapore
Michelle Yee: National University of Singapore
Priya Ragunathan: Nanyang Technological University
Joon Shin: Nanyang Technological University
Shashi Bhushan: Nanyang Technological University
Junhao Zhu: Harvard University
Tatos Akopian: Harvard University
Olga Kandror: Harvard University
Teck Kwang Lim: National University of Singapore
Martin Gengenbacher: Center for Discovery and Innovation, Hackensack Meridian Health
Qingsong Lin: National University of Singapore
Eric J. Rubin: Harvard University
Gerhard Grüber: Nanyang Technological University
Thomas Dick: National University of Singapore

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15516-1

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