## Mechanism of Rifampicin Resistance in TB **Key Point:** Mutations in the **rpoB gene** (encoding the β-subunit of bacterial RNA polymerase) account for **>95% of rifampicin-resistant TB** cases worldwide. ### Molecular Basis 1. **Rifampicin's target:** Binds to the β-subunit of bacterial RNA polymerase, inhibiting transcription 2. **rpoB mutations:** Point mutations (most commonly in the "rifampicin resistance-determining region" or RRDR, codons 426–452) alter the drug-binding pocket 3. **Result:** Rifampicin can no longer bind effectively, conferring high-level resistance ### Why This Matters Clinically **High-Yield:** Because rpoB mutations cause >95% of RIF resistance: - **Rapid molecular testing** (e.g., GeneXpert MTB/RIF) detects rpoB mutations to diagnose RIF-resistant TB within 2 hours - RIF resistance is a **surrogate marker for MDR-TB** in ~90% of cases (because INH resistance often co-occurs) - Detection of RIF resistance prompts immediate second-line therapy initiation **Mnemonic:** **RpoB = Rifampicin's Primary target** — mutations here cause >95% of resistance. ### Rare Resistance Mechanisms (<5%) | Mechanism | Frequency | Clinical Relevance | | --- | --- | --- | | rpoB mutations | >95% | Detected by GeneXpert, molecular assays | | Efflux pumps (porins) | <2% | Rare, not routinely tested | | Enzymatic inactivation | <1% | Very uncommon in TB | | Cell wall alterations | <1% | Not a primary mechanism | **Clinical Pearl:** A patient with TB who has a positive GeneXpert MTB/RIF result (indicating RIF resistance) has a >90% probability of also having INH resistance, making them MDR-TB until proven otherwise. [cite:Harrison 21e Ch 158, Robbins 10e Ch 8]
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