What is the primary mechanism of action of isoniazid against Mycobacterium tuberculosis?

• A. Inhibition of DNA gyrase.
• B. Inhibition of RNA polymerase.
• C. Inhibition of mycolic acid synthesis after activation by KatG.
• D. Disruption of peptidoglycan cross-linking.

Answer: (C)

Isoniazid works by targeting a feature unique to the mycobacterial cell wall: mycolic acids. It is a prodrug that must be activated by the bacterial enzyme KatG. Once activated, it forms a reactive complex that inhibits the enzyme InhA in the fatty acid synthase II system, blocking the synthesis of mycolic acids. Without these long lipid components, the cell wall becomes compromised, especially in actively growing bacteria, leading to cell death. This activation step by KatG and the specific blockade of mycolic acid production explain why isoniazid is effective against Mycobacterium tuberculosis.

Other options describe mechanisms used by different antibiotic classes—DNA gyrase inhibitors (like fluoroquinolones), RNA polymerase inhibitors (rifamycins), or agents that disrupt peptidoglycan cross-linking (beta-lactams, glycopeptides). They do not reflect how isoniazid works. Resistance often arises from mutations in KatG (reducing activation) or in the target pathway (e.g., InhA).