Isoniazid resistance in M. tuberculosis most commonly results from mutation in katG (catalase-peroxidase). This means INH resistance arises because:
- A KatG normally degrades toxic reactive oxygen species; its loss increases mycobacterial oxidative stress making INH-mediated killing unnecessary
- B KatG-derived reactive metabolites of INH directly alkylate the mycobacterial cell wall; mutation prevents alkylation
- C KatG normally activates INH to isonicotinoyl radical that forms adducts with NADH; katG mutation prevents activation, allowing enoyl-ACP reductase (InhA) to function normally ✓
- D KatG phosphorylates INH to its active pyridinium form; in its absence INH remains as an inactive prodrug permanently
Explanation
Isoniazid is a prodrug requiring oxidative activation by the mycobacterial catalase-peroxidase KatG. KatG oxidizes INH to an isonicotinoyl acyl radical, which then forms a covalent adduct with NADH (specifically INH-NADH). This INH-NADH adduct is a potent inhibitor of InhA (enoyl-acyl carrier protein reductase), an enzyme essential for mycolic acid synthesis (fatty acid elongation cycle). Mutations in katG prevent INH activation, so no INH-NADH adduct is formed, InhA remains functional, and mycolic acid synthesis continues normally. Resistance can also arise from InhA promoter mutations (overexpressing InhA, diluting the adduct effect) or inhA structural mutations.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.