What is the mechanism of action of isoniazid?

• A. Disrupts mycobacterial energy production by collapsing the proton motive force
• B. Inhibits bacterial DNA-dependent RNA polymerase
• C. Inhibits mycobacterial cell-wall mycolic acid synthesis after activation by the KatG enzyme
• D. Inhibits folate synthesis in mycobacteria

Answer: (C)

Isoniazid works as a prodrug that must be activated by the mycobacterial enzyme KatG. Once activated, it forms a complex with NAD that inhibits InhA, an enoyl-ACP reductase in the fatty acid synthase II pathway, blocking the synthesis of mycolic acids. Mycolic acids are essential long-chain components of the mycobacterial cell wall, so their disruption weakens the cell envelope and halts bacterial growth. This selective target is why isoniazid is particularly effective against Mycobacterium tuberculosis. Resistance often arises from mutations in KatG that prevent activation, or changes in InhA that reduce drug binding. Other antitubercular drugs act on different targets, such as RNA polymerase or cell-wall components, which is why this mechanism stands apart.