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, Thomas Dick
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.