The mechanism of pyrazinamide (PZA) resistance in Mycobacterium tuberculosis most commonly involves mutations in which gene, and why does PZA have NO activity at neutral pH in vitro?

• A rpoB gene mutations; PZA requires acid pH in macrophage phagosomes to be converted to active pyrazinoic acid by bacterial pyrazinamidase
• B katG gene mutations; PZA requires mycobacterial catalase-peroxidase activation
• C pncA gene mutations encoding pyrazinamidase; PZA requires acid pH for pyrazinamidase activity and conversion to pyrazinoic acid, which then disrupts mycobacterial membrane potential ✓
• D inhA gene mutations; PZA is a pro-drug activated by InhA enzyme within mycobacterial cytoplasm

Explanation

Pyrazinamide (PZA) is a prodrug that must be converted to pyrazinoic acid by mycobacterial pyrazinamidase, encoded by the pncA gene. This enzyme functions optimally at acidic pH (pH 5.0–5.5), as found inside activated macrophage phagolysosomes — explaining PZA's unique activity against dormant/intracellular mycobacteria and its sterilizing effect. At neutral pH in vitro, pyrazinamidase activity is low, PZA is not converted efficiently, and no antibacterial activity is observed. Resistance most commonly arises from pncA mutations (>70% of resistant strains), which inactivate pyrazinamidase. Active pyrazinoic acid disrupts mycobacterial membrane energetics and trans-translation. katG mutation causes isoniazid resistance.

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

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