Pyrazinamide is only active at acidic pH (pH 5.0–5.5) and is particularly effective against dormant intracellular mycobacteria. The reason for pH dependence is:

• A Pyrazinamide is a prodrug converted by pyrazinamidase to pyrazinoic acid, which is protonated at low pH and accumulates inside bacteria ✓
• B Acidic pH increases the binding affinity of pyrazinamide to its target ribosomal protein S1 (RpsA)
• C Low pH induces expression of pyrazinamide efflux pumps that prevent drug resistance
• D Acidic conditions directly convert pyrazinamide to the toxic peroxynitrite radical

Explanation

Pyrazinamide diffuses into mycobacteria and is hydrolyzed by intrabacterial pyrazinamidase (encoded by pncA) to pyrazinoic acid (POA). At acidic pH (as found in macrophage phagolysosomes), POA is protonated to HPOA, which easily re-enters the bacterial cell and accumulates to toxic concentrations. POA inhibits the fatty acid synthase I system and has other effects on membrane potential. Resistance most commonly results from mutations in pncA impairing pyrazinamidase activity.

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

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Written and medically reviewed by the StethoPrep medical team.