Pyrazinamide (PZA) is uniquely active against intracellular, 'dormant' mycobacteria in acidic macrophage phagolysosomes but inactive at neutral pH. This is because:

• A PZA directly inhibits mycolic acid synthesis at acidic pH
• B PZA requires bacterial pyrazinamidase (PncA) to convert it to pyrazinoic acid, which is protonated at low pH and accumulates intracellularly, disrupting membrane potential ✓
• C PZA is a prodrug converted by host macrophage enzymes to pyrazinoic acid at low pH
• D PZA inhibits fatty acid synthase I (FasI) only when it is protonated at acidic pH

Explanation

Pyrazinamide enters mycobacteria and is hydrolysed by the bacterial enzyme pyrazinamidase (encoded by pncA) to pyrazinoic acid (POA). At the acidic pH of lysosomes, POA becomes protonated (POAH) and cannot be efficiently exported, accumulating to bactericidal concentrations; it disrupts mycobacterial membrane potential and inhibits the fatty acid synthase I (FasI). PZA resistance is most commonly due to mutations in pncA, abrogating pyrazinamidase activity.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.