Pyrazinamide (PZA) is a key sterilising drug in TB treatment but is only active in an acidic environment. This is because:

• A PZA requires alkaline pH to penetrate the waxy mycobacterial cell wall
• B PZA is converted to pyrazinoic acid by bacterial pyrazinamidase, and pyrazinoic acid inhibits fatty acid synthase I (FAS-I) selectively under acidic pH ✓
• C PZA is activated by rifampicin-inducible CYP2E1 in acidic lysosomes
• D PZA inhibits ATP synthase in mycobacteria only when bacterial cytoplasm is acidic

Explanation

Pyrazinamide is a prodrug hydrolysed by mycobacterial pyrazinamidase (pncA gene product) to pyrazinoic acid (POA). POA accumulates in acidic environments (pH < 6) because its protonated form (HPOA) diffuses into the bacterium more readily and cannot exit as efficiently. HPOA inhibits fatty acid synthase I (FAS-I), disrupting mycobacterial cell membrane synthesis. PZA is uniquely effective against semi-dormant bacilli in the acidic intracellular environment of macrophage phagolysosomes, making it essential in the first two months for sterilising treatment. ATP synthase inhibition is the mechanism of bedaquiline.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.