Rifampicin resistance in M. tuberculosis results from mutations in the rpoB gene. Rifampicin binds to the beta subunit of RNA polymerase. Which statement correctly explains how the specific rpoB mutation at codon 531 (Ser531Leu) confers resistance without impairing mycobacterial fitness?

• A The Ser531Leu mutation disrupts a disulfide bridge in the rifampicin binding pocket, causing the drug to exit rapidly while gene transcription is unaffected
• B The Ser531Leu mutation changes the drug-binding pocket shape so rifampicin can no longer make stable hydrogen bond contacts, reducing binding affinity by 1000-fold while the mutant RNA polymerase retains near-normal transcriptional activity ✓
• C Ser531Leu mutation phosphorylates rifampicin, inactivating it before it can bind the RNA polymerase active site
• D The mutation causes overexpression of rifampin-metabolizing esterases that cleave the ansa chain before the drug reaches its target

Explanation

Rifampicin binds to a pocket in the beta subunit of bacterial RNA polymerase (encoded by rpoB), blocking the initiation-to-elongation transition by sterically blocking the RNA exit channel. The Ser531 residue makes critical hydrogen bond contacts with the rifampicin hydroxyl groups. The Ser531Leu substitution replaces the polar serine (capable of H-bonding) with hydrophobic leucine, eliminating critical hydrogen bond contacts with rifampicin and drastically reducing drug-binding affinity. Crucially, the S531L mutant RNA polymerase retains near-normal transcriptional activity because the residue is not directly in the active catalytic site but in the drug-binding pocket adjacent to it. This mutation accounts for approximately 45% of rifampicin resistance worldwide and is used as a surrogate marker for MDR-TB in molecular tests (GeneXpert).

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

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