Which of the following anti-tuberculous drugs is a prodrug that requires activation by the bacterial catalase-peroxidase enzyme KatG?

Explanation

## Isoniazid: Mechanism of Action **Key Point:** Isoniazid (INH) is a prodrug that must be activated intracellularly by the mycobacterial enzyme catalase-peroxidase (KatG) to exert its bactericidal effect. ### Activation Mechanism Isoniazid itself is inactive. Once inside the tubercle bacillus, KatG converts INH to its active form, which then inhibits mycolic acid synthesis by binding to InhA (enoyl-ACP reductase). This dual requirement—both drug uptake AND enzymatic activation—explains why: 1. **KatG-deficient mutants** develop INH resistance 2. **Catalase-negative strains** (e.g., *M. bovis*) are intrinsically resistant to INH 3. INH has **no activity against extracellular bacilli** (only intracellular activation works) ### High-Yield Clinical Correlate **High-Yield:** Approximately 50–80% of INH-resistant TB strains have mutations in the *katG* gene, making this the most common mechanism of INH resistance globally. The remaining resistance is due to *inhA* promoter mutations. ### Comparison with Other First-Line Drugs | Drug | Activation Required? | Primary Target | | --- | --- | --- | | **Isoniazid** | Yes (KatG) | Mycolic acid synthesis (InhA) | | **Rifampicin** | No | RNA polymerase (direct inhibitor) | | **Pyrazinamide** | Yes (pyrazinamidase) | Mycobacterial membrane, energy metabolism | | **Ethambutol** | No | Arabinosyl transferase (direct inhibitor) | **Clinical Pearl:** The KatG-dependent activation of INH is why the drug is effective only against *actively metabolizing* mycobacteria—dormant bacilli with low KatG expression may survive INH therapy, necessitating prolonged treatment courses.