Pyrazinamide triggers degradation of its target aspartate decarboxylase

• Main Authors: Gopal, Pooja, Sarathy, Jickky Palmae, Yee, Michelle, Ragunathan, Priya, Shin, Joon, Bhushan, Shashi, Zhu, Junhao, Akopian, Tatos, Kandror, Olga, Lim, Teck Kwang, Gengenbacher, Martin, Lin, Qingsong, Rubin, Eric J., Grüber, Gerhard, Dick, Thomas
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2020
• Subjects: Science::Biological sciences::Biochemistry; Science::Biological sciences::Molecular biology; Target Identification; Tuberculosis
• Online Access: https://hdl.handle.net/10356/138824
• Institution: Nanyang Technological University

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.