A patient with drug-resistant leprosy is found to have a mutation in the folP1 gene of M. leprae. Which anti-leprosy drug does this resistance affect, and what is the mechanism?

• A Dapsone — folP1 encodes dihydropteroate synthase (DHPS); mutations prevent competitive binding of dapsone to the enzyme's PABA-binding site ✓
• B Rifampicin — folP1 encodes DNA-dependent RNA polymerase; mutations prevent rifampicin from binding the beta subunit
• C Clofazimine — folP1 encodes the target electron transport complex; mutations allow bypass of clofazimine's inhibitory site
• D Ofloxacin — folP1 encodes type II topoisomerase; gyrase mutations confer fluoroquinolone resistance in M. leprae

Explanation

Dapsone (4,4'-diaminodiphenyl sulfone) is a structural analogue of para-aminobenzoic acid (PABA) and inhibits dihydropteroate synthase (DHPS) — the enzyme that condenses PABA with dihydropterin to form dihydropteroic acid in the folate synthesis pathway of M. leprae (which cannot salvage exogenous folate). The M. leprae DHPS gene is folP1. Point mutations in folP1 (particularly at codons Pro55Leu and Thr53Ala) alter the PABA-binding site, reducing dapsone's affinity and conferring resistance. This is confirmed by genotypic drug susceptibility testing since M. leprae cannot be cultured in vitro. Primary dapsone resistance is now monitored in national programmes through folP1 sequencing of biopsy specimens.

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

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