A patient with pulmonary tuberculosis is found to have an M. tuberculosis isolate resistant to both rifampicin and isoniazid on drug susceptibility testing (DST). This qualifies as MDR-TB. The molecular mechanism of rifampicin resistance in M. tuberculosis most commonly involves:
- A Mutations in the rpoB gene encoding the beta-subunit of RNA polymerase, in the 81-bp rifampicin resistance-determining region (RRDR) ✓
- B Overexpression of the Rv1258c efflux pump in the tapABC operon
- C Mutations in the katG gene causing loss of catalase-peroxidase activity
- D Mutations in the inhA promoter reducing NADH-dependent enoyl-ACP reductase binding
Explanation
More than 95% of rifampicin-resistant M. tuberculosis strains carry mutations in a defined 81-bp region (codons 507–533) of rpoB, encoding the beta-subunit of RNA polymerase — the drug's target. The most common mutation is Ser531Leu (His526 and Asp516 are also frequent). Rifampicin inhibits transcription by blocking the RNA polymerase elongation complex; mutations in rpoB prevent binding. katG mutations and inhA promoter mutations are responsible for isoniazid resistance (katG causes high-level INH resistance; inhA promoter causes low-level resistance). Efflux pumps contribute to resistance but are not the dominant rifampicin resistance mechanism.
Reference: Ananthanarayan & Paniker's Textbook of Microbiology, 11th ed.
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