Isoniazid and ethionamide share a common target in the mycolic acid synthesis pathway. What accounts for their cross-resistance?

• A Both are activated by KatG; KatG mutations inactivate both drugs
• B Both are activated by ethA; ethA mutations inactivate both drugs
• C Both target the rpoB gene; identical mutations confer resistance to both
• D Both target InhA (enoyl-ACP reductase); mutations in the inhA promoter region confer low-level resistance to both ✓

Explanation

Ethionamide, like isoniazid, targets InhA (enoyl-ACP reductase) in the mycolic acid synthesis pathway. Both drugs are prodrugs activated by different enzymes (KatG for INH, ethA for ethionamide), but mutations in the inhA promoter or structural gene cause overexpression or reduced binding of both drugs, conferring cross-resistance. However, KatG mutations cause INH resistance without ethionamide cross-resistance since activation pathways differ.

Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.

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