What is the most common genetic mechanism of resistance to rifampin in Mycobacterium tuberculosis?

• A. Overexpression of efflux pumps for rifampin.
• B. Mutations in katG.
• C. Decreased permeability of the cell wall to rifampin.
• D. Mutations in the rpoB gene encoding the beta subunit of RNA polymerase.

Answer: (D)

Rifampin’s action is to block bacterial RNA synthesis by binding to the beta subunit of RNA polymerase, which is encoded by the rpoB gene. The most common mechanism of resistance in Mycobacterium tuberculosis is mutations in rpoB, particularly in the rifampin resistance-determining region. These mutations change the shape or chemistry of the beta subunit so rifampin can no longer bind effectively, allowing transcription to continue despite the presence of the drug. Because these rpoB mutations reliably arise and account for the majority of rifampin-resistant TB cases, they are the primary and most consistent way the bacterium evades rifampin.

Other possibilities, like overexpression of efflux pumps, can contribute to resistance for some drugs but are not the main driver for rifampin in TB. Mutations in katG cause isoniazid resistance, not rifampin. Decreased cell wall permeability is not the principal mechanism for rifampin resistance in Mycobacterium tuberculosis.