In leprosy, the mechanism of dapsone resistance involves mutations that lead to overproduction of which enzyme, allowing competitive displacement of dapsone?

• A Dihydropteroate synthase (DHPS) with structural mutations reducing dapsone affinity ✓
• B Dihydrofolate reductase (DHFR) increasing tetrahydrofolate regeneration
• C Thymidylate synthase overexpression bypassing dapsone-induced folate depletion
• D Acetyl-CoA carboxylase mutation reducing fatty acid dependence on para-aminobenzoic acid

Explanation

Dapsone (and other sulfones) competitively inhibit dihydropteroate synthase (DHPS), the enzyme that incorporates para-aminobenzoic acid (PABA) into dihydropteroate — a folate precursor. Resistance in Mycobacterium leprae arises from point mutations in the folP1 gene encoding DHPS, particularly in the PABA/substrate binding site, which reduce the enzyme's affinity for dapsone while retaining affinity for PABA. This allows PABA to competitively displace dapsone even at therapeutic concentrations. DHFR mutations are relevant for trimethoprim resistance (option B).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.