Isoniazid resistance in M. tuberculosis most commonly arises from mutations in which gene, and what is the consequence of this mutation?

• A inhA gene promoter mutation, overexpressing enoyl-ACP reductase and overcoming drug inhibition
• B katG gene (encoding catalase-peroxidase), preventing pro-drug activation to isonicotinoyl radical ✓
• C kasA gene encoding beta-ketoacyl-ACP synthase, altering drug binding site
• D ndh gene encoding NADH dehydrogenase-2, increasing NADH and competing with drug-NAD adduct

Explanation

The most common mechanism of isoniazid resistance (seen in ~50-70% of resistant isolates globally) is mutation in the katG gene, which encodes the catalase-peroxidase enzyme responsible for activating isoniazid pro-drug to the reactive isonicotinoyl radical. Loss of KatG function prevents formation of the isonicotinoyl-NAD adduct that inhibits InhA. The second most common mechanism (~20-30%) is overexpression of InhA due to inhA promoter mutations, which dilutes the drug-NAD adduct effect. KasA and ndh mutations are less common contributory mechanisms. Clinically, katG mutations confer high-level INH resistance whereas inhA promoter mutations confer low-level resistance and predict ethionamide co-resistance.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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