A 38-year-old man from rural Maharashtra presents with a 4-month history of persistent cough, fever, and weight loss despite 2 months of standard first-line anti-TB therapy. Sputum smear microscopy remains positive. Drug susceptibility testing reveals resistance to both isoniazid and rifampicin. Which is the most common mechanism of resistance to rifampicin in MDR-TB?

Explanation

## Mechanism of Rifampicin Resistance in MDR-TB **Key Point:** Mutations in the *rpoB* gene (encoding the β-subunit of bacterial RNA polymerase) account for >95% of rifampicin-resistant TB globally, including India. ### Why rpoB Mutations Are Predominant Rifampicin binds directly to the β-subunit of *Mycobacterium tuberculosis* RNA polymerase and inhibits transcription. Point mutations in the *rpoB* gene—particularly in the "rifampicin-binding pocket" (codons 426–452)—prevent drug binding and confer high-level resistance. **High-Yield:** The most frequent mutations occur at: - Codon 450 (Ser → Leu) - Codon 445 (His → Asp) - Codon 451 (Asp → Asn) These mutations are detectable by rapid molecular assays (Xpert MTB/RIF, line probe assays) used for MDR-TB diagnosis. ### Alternative (Rare) Mechanisms | Mechanism | Frequency | Organism Note | |-----------|-----------|---------------| | rpoB mutations | >95% | M. tuberculosis | | Efflux pumps | <5% | More common in non-tuberculous mycobacteria | | Enzymatic inactivation | Extremely rare | Not documented in TB | | Altered permeability | Not established | Not a primary mechanism | **Clinical Pearl:** In India, where TB burden is high and MDR-TB prevalence is significant, rapid *rpoB* mutation detection is now standard practice for early identification of MDR cases and prompt initiation of second-line therapy. **Warning:** Do not confuse rifampicin resistance mechanisms with those of other drugs (e.g., isoniazid resistance via *katG* or *inhA* mutations).