Isoniazid (INH) requires activation by mycobacterial catalase-peroxidase (KatG). The final toxic intracellular target and mechanism of bactericidal action of activated INH is:
- A Alkylation of mycobacterial DNA guanine residues causing lethal strand breaks
- B Formation of an isonicotinoyl-NAD adduct that inhibits InhA (NADH-dependent enoyl-ACP reductase), blocking fatty acid elongation in mycolic acid synthesis ✓
- C Inhibition of arabinosyltransferase preventing polymerization of arabinogalactan in the cell wall
- D Inhibition of dihydropteroate synthase reducing folate synthesis in mycobacteria
Correct answer: B. Formation of an isonicotinoyl-NAD adduct that inhibits InhA (NADH-dependent enoyl-ACP reductase), blocking fatty acid elongation in mycolic acid synthesis
Explanation
KatG activates INH to an isonicotinoyl radical that reacts with NAD+ (or NADP+) to form isonicotinoyl-NAD(P) adducts. This adduct is a tight-binding competitive inhibitor of InhA (2-trans-enoyl-ACP reductase), an enzyme essential for elongation of C26 fatty acids to C56 meromycolic acids during mycolic acid biosynthesis. Inhibition of mycolic acid production disrupts the unique mycobacterial cell wall. Resistance most commonly arises from katG mutations (loss of activation) or inhA promoter mutations (overexpression of target).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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