## Isoniazid Activation Mechanism **Key Point:** Isoniazid (INH) is a prodrug that must be activated intracellularly by the mycobacterial enzyme catalase-peroxidase (KatG) to exert its bactericidal effect. ### Mechanism of Action 1. **Prodrug activation**: INH enters the mycobacterial cell and is oxidized by KatG to form an INH-NAD adduct 2. **Target inhibition**: The activated INH-NAD complex inhibits mycobacterial DNA gyrase and mycolic acid synthesis 3. **Bactericidal effect**: This leads to disruption of the mycobacterial cell wall ### Clinical Significance **High-Yield:** KatG-deficient mutants of *Mycobacterium tuberculosis* are resistant to isoniazid despite intact drug-metabolizing enzymes. This is a major mechanism of INH resistance. **Clinical Pearl:** Patients with slow acetylator phenotype have higher INH levels and increased risk of peripheral neuropathy (preventable with pyridoxine 10 mg daily). ### Comparison with Other First-Line Drugs | Drug | Activation Required | Primary Target | Bactericidal/Static | | --- | --- | --- | --- | | Isoniazid | Yes (KatG) | Mycolic acid synthesis | Bactericidal | | Rifampicin | No | RNA polymerase | Bactericidal | | Pyrazinamide | Yes (PZase) | Fatty acid synthesis | Bactericidal | | Ethambutol | No | Arabinan synthesis | Bacteriostatic | **Mnemonic:** **INH = KatG-dependent** — Remember that INH needs the bacterial enzyme KatG (catalase-peroxidase) to become active, making it unique among first-line agents.
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