Which antitubercular drug is a prodrug that requires activation by the bacterial enzyme catalase-peroxidase (KatG) to exert its bactericidal effect?

Explanation

## Isoniazid: Mechanism of Action **Key Point:** Isoniazid (INH) is a prodrug that must be activated intracellularly by the mycobacterial enzyme catalase-peroxidase (encoded by the *katG* gene) to form an isonicotinoyl radical, which then inhibits mycolic acid synthesis by targeting InhA (enoyl-ACP reductase). ### Activation Pathway 1. INH enters the mycobacterial cell 2. KatG enzyme oxidizes INH to the active isonicotinoyl radical 3. The radical binds to NAD^+^ to form an INH-NAD adduct 4. This adduct inhibits InhA, blocking mycolic acid synthesis 5. Mycolic acids are essential for cell wall integrity → bactericidal effect **High-Yield:** Mutations in *katG* or *inhA* genes confer INH resistance — this is the most common mechanism of resistance in *Mycobacterium tuberculosis*. ### Why This Matters Clinically - INH is bactericidal against actively dividing mycobacteria - Most effective in the first 2 weeks of treatment - Excellent intracellular penetration and CSF penetration (critical for TB meningitis) - Rapid resistance development if used as monotherapy **Clinical Pearl:** INH is the cornerstone of first-line TB therapy because of its potency, penetration, and low cost. However, slow-growing or non-replicating bacilli may escape INH killing, necessitating combination therapy. [cite:KD Tripathi 8e Ch 52]