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.

中文翻译：

---

吡嗪酰胺触发其目标天冬氨酸脱羧酶的降解。

吡嗪酰胺是一种杀菌的一线结核药物。先前的遗传，代谢组学和生物物理分析表明，吡嗪酸（前药吡嗪酰胺（PZA）的生物活性形式）通过与天冬氨酸脱羧酶PanD结合而中断了结核分枝杆菌中辅酶A的生物合成。尽管大多数药物通过抑制靶标结合后的蛋白质功能起作用，但我们在这里发现吡嗪酸只是一种弱酶抑制剂。我们显示吡嗪酸与PanD的结合触发酪蛋白水解蛋白酶ClpC1-ClpP降解蛋白质。因此，旧的结核病药物吡嗪酰胺通过充当靶标降解物发挥抗菌活性，这种作用机理最近已成为跨疾病适应症的药物发现的成功策略。