## Mechanism of Isoniazid Activation **Key Point:** Isoniazid is a prodrug that must be activated intracellularly by the mycobacterial enzyme catalase-peroxidase (KatG) to exert its bactericidal effect. ### Activation Pathway Isoniazid enters *Mycobacterium tuberculosis* passively and is converted by KatG into an isonicotinic acyl radical, which then forms a complex with NAD^+^. This INH-NAD adduct inhibits mycobacterial enoyl-ACP reductase (InhA), blocking mycolic acid synthesis — a critical component of the mycobacterial cell wall. ### Clinical Significance **High-Yield:** Mutations in the *katG* gene or deficiency of KatG enzyme is a major mechanism of isoniazid resistance in *M. tuberculosis*. This is why isoniazid-resistant strains often show reduced catalase activity (negative niacin test). ### Comparison with Other First-Line Agents | Drug | Activation Required | Mechanism | |------|--------------------|-----------| | Isoniazid | Yes (KatG) | Inhibits mycolic acid synthesis | | Rifampicin | No | Directly inhibits RNA polymerase | | Pyrazinamide | Yes (PZase) | Inhibits fatty acid synthesis | | Ethambutol | No | Directly inhibits arabinosyl transferases | **Clinical Pearl:** Patients with KatG-deficient strains may remain isoniazid-susceptible on standard susceptibility testing but show clinical treatment failure — a phenomenon called "discordant resistance." [cite:KD Tripathi 8e Ch 51]
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