Pyrazinamide is uniquely active in acidic environments (within macrophage phagolysosomes). Its mechanism depends on conversion to pyrazinoic acid by pyrazinamidase (PncA enzyme). Resistance is most commonly caused by:

• A Mutations in the pncA gene encoding pyrazinamidase, preventing conversion of pyrazinamide prodrug to its active form, pyrazinoic acid ✓
• B Upregulation of efflux pump RpsA that exports pyrazinoic acid before it can inhibit fatty acid biosynthesis
• C Upregulation of mycobacterial alkaline phosphatase that neutralises the acidic environment in phagolysosomes
• D Amplification of the RpsA gene encoding the ribosomal protein S1 target of pyrazinoic acid

Explanation

Pyrazinamide is a prodrug that requires intracellular activation by mycobacterial pyrazinamidase (encoded by pncA). In the acidic pH of phagolysosomes, pyrazinoic acid is protonated (HPOA) and enters the bacillus, inhibiting fatty acid synthase I (FAS-I) and disrupting membrane potential. Mutations in pncA (found in >70% of PZA-resistant M. tuberculosis) abolish enzyme activity, preventing activation. This is the most common resistance mechanism. Note: Phenotypic susceptibility testing for PZA is technically difficult (requires acidic media) and molecular pncA sequencing is increasingly used for resistance detection.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.