Which drug is activated by the KatG enzyme to exert its effect?

• A. Isoniazid
• B. Rifampin
• C. Ethambutol
• D. Pyrazinamide

Answer: (A)

Isoniazid is a prodrug that must be activated by the mycobacterial KatG catalase-peroxidase. Once KatG activates it, the resulting metabolite inhibits the enoyl-ACP reductase InhA, blocking mycolic acid synthesis in the cell wall. This disruption of the fatty acid synthesis I pathway is lethal to actively growing mycobacteria. Resistance often arises from mutations in KatG that reduce activation, which is why this activation step is so important clinically.

The other drugs work differently and don’t depend on KatG activation: rifampin targets bacterial RNA polymerase; ethambutol inhibits arabinosyl transferases essential for cell wall synthesis; pyrazinamide is activated by pyrazinamidase (PncA) to pyrazinoic acid, and its action is related to acidic environments and membrane effects rather than KatG activation.