Pyrazinamide is uniquely active against semi-dormant intracellular bacilli in acidic environments. Its mechanism of action requires bacterial pyrazinamidase (PZase). In drug-resistant TB, PZase-encoding gene mutations most frequently occur in:

• A rpoB gene on the beta subunit of RNA polymerase
• B pncA gene encoding nicotinamidase/pyrazinamidase, which converts pyrazinamide to the active form pyrazinoic acid ✓
• C inhA gene encoding enoyl-ACP reductase, the primary target of pyrazinoic acid
• D katG gene encoding catalase-peroxidase required for pyrazinamide activation

Explanation

Pyrazinamide is converted by bacterial nicotinamidase/pyrazinamidase (encoded by pncA) to pyrazinoic acid, the active form. Pyrazinoic acid disrupts membrane energetics, inhibits fatty acid synthesis (FAS I and translation-related aspects), and acidifies the bacterial cytoplasm in the already-acidic phagosomal environment. Mutations in pncA (observed in >90% of PZA-resistant clinical isolates) abolish enzyme activity, preventing prodrug conversion. rpoB mutations confer rifampicin resistance; katG mutations confer isoniazid resistance; inhA gene mutations confer isoniazid (and ethionamide) resistance.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.