Pyrazinamide has activity exclusively against Mycobacterium tuberculosis and not against other mycobacteria because of a species-specific mechanism. Resistance occurs when:

• A Mutations in pncA (pyrazinamidase gene) prevent conversion of pyrazinamide to pyrazinoic acid, the active form required for disruption of membrane potential and CoA biosynthesis ✓
• B Mutations in rpoB reduce affinity for pyrazinoic acid, the active form
• C Upregulation of efflux pumps encoded by mfpA removes pyrazinoic acid before it reaches the target
• D Mutations in inhA reduce binding of pyrazinoic acid to the InhA enoyl reductase target

Explanation

Pyrazinamide is a prodrug. M. tuberculosis possesses a specific pyrazinamidase (encoded by pncA) that converts pyrazinamide to pyrazinoic acid (POA). At the acidic pH of phagolysosomes, protonated POA (pPOA) enters mycobacteria and disrupts membrane potential, inhibits trans-membrane transport, and inhibits fatty acid synthase I (FASI) needed for CoA biosynthesis. Most resistant M. tuberculosis strains (>90%) have pncA mutations that abolish pyrazinamidase activity, preventing POA formation. Non-tuberculous mycobacteria naturally lack or have non-functional pncA, explaining pyrazinamide's species-specificity.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.