## Mechanisms of Drug Resistance in MDR-TB ### Correct Mechanisms **Key Point:** MDR-TB resistance arises from specific chromosomal mutations affecting drug activation and target binding. Understanding these mechanisms is critical for diagnosis and treatment selection. | Drug | Gene(s) Mutated | Mechanism | Frequency | |------|-----------------|-----------|----------| | Isoniazid | katG, inhA, fabG1 | Loss of catalase-peroxidase activation (katG ~95%); inhA overexpression | ~95% katG mutations | | Rifampicin | rpoB | Altered RNA polymerase β-subunit binding pocket | ~95% of RIF-R cases | | Fluoroquinolones | gyrA, gyrB | DNA gyrase mutations reduce drug binding | Common in XDR-TB | | Pyrazinamide | pncA | Loss of pyrazinamidase enzyme; cannot convert prodrug to active form | ~90% of PZA-R | ### Why Option 4 is Incorrect **High-Yield:** Pyrazinamide resistance is **NOT** primarily due to efflux pump activity. Instead, it results from: 1. **pncA gene mutations** (~90% of cases) — loss of pyrazinamidase enzyme that converts PZA (prodrug) to pyrazinoic acid (active form) 2. Rarely: mutations in the rpsA gene (ribosomal protein S1) affecting pyrazinoic acid uptake Efflux pumps play a minor role in PZA resistance and are not the primary mechanism. This is a common misconception in TB drug resistance. ### Clinical Pearl **Key Point:** Detection of rpoB mutations by molecular methods (GeneXpert MTB/RIF, line probe assays) is the gold standard for rapid MDR-TB diagnosis in India, as per NTEP guidelines. Simultaneous detection of katG/inhA mutations confirms INH resistance. ### Mnemonic **TB Drug Resistance Genes — "KIR-FQ-P":** - **K** = katG (Isoniazid) - **I** = inhA (Isoniazid alternative) - **R** = rpoB (Rifampicin) - **FQ** = gyrA/gyrB (Fluoroquinolones) - **P** = pncA (Pyrazinamide)
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