Mycobacterium tuberculosis metabolic and stress-response enzymes affected by pyrazinoic acid

Mycobacterium tuberculosis metabolic and stress-response enzymes affected by pyrazinoic acid refers to a group of essential proteins targeted by the active form of the first-line antitubercular drug pyrazinamide (PZA). Pyrazinamide is a prodrug that is converted into pyrazinoic acid (POA) by the mycobacterial enzyme pyrazinamidase (PncA) [1.1.2]. Once activated, POA exerts its bactericidal and sterilizing effects by inhibiting multiple targets, most notably aspartate 1-decarboxylase (PanD), which is critical for coenzyme A (CoA) biosynthesis [1.2.1]. POA binding to PanD induces its degradation by the ClpC1-ClpP protease complex, leading to CoA depletion and metabolic failure [1.2.4, 1.2.5]. Other significant targets include ribosomal protein S1 (RpsA), which is involved in the ribosome-rescuing process of trans-translation, and Rv2783, a protein that regulates the stringent response by metabolizing ppGpp [1.1.2, 1.1.4]. These multi-target interactions, combined with the disruption of membrane energetics at acidic pH, allow PZA to effectively kill both actively growing and persistent mycobacteria within host lesions [1.3.3, 1.4.4]. Resistance is primarily mediated by mutations in the pncA gene, which prevents prodrug activation, or by mutations in the target genes themselves, such as panD and rpsA [1.2.2, 1.4.3].

Other names

Pyrazinamide targetsPOA targetsPanDRpsARv2783FasIAspartate 1-decarboxylaseRibosomal protein S1PNPase

Pyrazinamide is a prodrug converted by mycobacterial pyrazinamidase (PncA) into pyrazinoic acid (POA) [1.1.2, 1.3.4]. POA acts as a multi-target inhibitor: it binds to PanD and triggers its degradation via the ClpC1-ClpP protease complex (inhibiting CoA synthesis) [1.2.1, 1.2.4], binds to RpsA to inhibit trans-translation (ribosome rescue) [1.1.4, 1.2.2], and inhibits Rv2783 to disrupt the ppGpp-mediated stringent response [1.1.2, 1.3.1]. Additionally, POA disrupts the bacterial membrane potential and inhibits membrane transport, particularly under acidic conditions [1.3.3].