Mycobacterium tuberculosis targets of pyrazinamide (PZA targets)

Pyrazinamide (PZA) is a cornerstone of first-line tuberculosis therapy, uniquely effective against semi-dormant Mycobacterium tuberculosis (Mtb) in acidic environments [1, 4]. It is a prodrug converted by the mycobacterial enzyme pyrazinamidase (PncA) into its active form, pyrazinoic acid (POA) [1, 2, 3]. POA exerts its antibacterial effects through multiple mechanisms, primarily by binding to and triggering the degradation of aspartate 1-decarboxylase (PanD), thereby disrupting coenzyme A biosynthesis [1, 6, 7]. Additionally, POA has been shown to inhibit trans-translation by binding to ribosomal protein S1 (RpsA) and to interfere with protein degradation via the ClpC1 chaperone [3, 6, 8, 9]. Beyond specific protein targets, POA acts as a protonophore that disrupts the bacterial membrane potential and lowers intracellular pH [1, 2, 4, 5]. Resistance to PZA is most commonly caused by mutations in the pncA gene, but mutations in panD, rpsA, and clpC1 also contribute to resistance in clinical isolates [3, 7, 8, 9].

Other names

Pyrazinoic acid targetsPZA targetsAspartate 1-decarboxylase (PanD)Ribosomal protein S1 (RpsA)ATP-dependent chaperone ClpC1Fatty acid synthase I (FAS I)

Pyrazinamide is a prodrug activated by the mycobacterial enzyme pyrazinamidase (PncA) into pyrazinoic acid (POA) [1, 2, 3]. POA inhibits multiple targets: it binds to aspartate 1-decarboxylase (PanD) and triggers its degradation, inhibiting coenzyme A biosynthesis [1, 6, 7]; it binds to ribosomal protein S1 (RpsA) to inhibit trans-translation [3, 6, 8, 9]; and it disrupts membrane potential and pH homeostasis by acting as a protonophore [1, 2, 4, 5].