Pyrazinamide is uniquely active in killing dormant, semi-dormant bacilli in acidic environments (e.g., within macrophages). Its mechanism requires:

• A Conversion to pyrazinoic acid (POA) by mycobacterial pyrazinamidase (PncA), which acidifies the bacterial cytoplasm and disrupts membrane potential and CoA synthesis at pH <6 ✓
• B Direct alkylation of mycobacterial DNA at physiological pH
• C Inhibition of mycolic acid synthesis by disrupting the enoyl-ACP reductase (InhA)
• D Inhibition of ATP synthase, depleting mycobacterial energy reserves

Explanation

Pyrazinamide is a prodrug: it enters mycobacteria and is converted to pyrazinoic acid (POA) by the enzyme pyrazinamidase encoded by pncA. POA accumulates in the acidic intracellular environment of macrophages, protonates to HPOA, and disrupts the mycobacterial membrane potential and acidifies the cytoplasm, inhibiting fatty acid synthesis (FAS-I) and CoA biosynthesis. Resistance arises almost entirely from pncA mutations. InhA inhibition is the mechanism of isoniazid/ethionamide; ATP synthase inhibition is the mechanism of bedaquiline.

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

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Written and medically reviewed by the StethoPrep medical team.