3.1 Antibiotic Resistance in MDR TB

MDR-TB (Multidrug Resistant Tuberculosis) is resistant to at least two of the most potent first-line antibiotics: isoniazid and rifampicin. This resistance emerges due to mutations in specific genes that alter the targets of these drugs or affect drug uptake and activation. Here's an in-depth look at the genetic mechanisms:

Isoniazid Resistance (inhA and katG mutations)

1. KatG Gene Mutation: Isoniazid is a prodrug that requires activation by the KatG enzymeA biological catalyst that speeds up chemical reactions in cells. (a catalase-peroxidase) in Mycobacterium tuberculosis. Mutations in the katG gene, particularly at position S315T, significantly reduce the activation of isoniazid, rendering it ineffective. This is one of the most common mechanisms for isoniazid resistance.

2. InhA Gene Mutation: In some cases, resistance is associated with mutations in the inhA gene, which encodes the target of activated isoniazid, enoyl-ACP reductase. Mutations in the promoter region of inhA lead to overexpression of the enzyme, decreasing the drug’s efficacy.

Rifampicin Resistance (rpoB mutation)

1. Rifampicin targets the RNA polymerase enzyme, which is crucial for bacterial RNA synthesis. Resistance to rifampicin occurs mainly due to mutations in the rpoB gene, which encodes the β-subunit of RNA polymerase. Mutations in the "rifampicin resistance-determining region" (RRDR) of rpoB cause structural changes in RNA polymerase, preventing rifampicin from binding effectively, thus inhibiting its action.

Efflux Pumps and Permeability Barriers

1. Some resistant strains upregulate efflux pumps, which actively transport antibiotics out of the bacterial cell, reducing the intracellular concentration of the drug. Mutations or overexpression of efflux pump genes such as Rv1258c and Rv1634 have been associated with MDR-TB. Additionally, Mycobacterium tuberculosis has a highly impermeable cell wallA rigid outer layer that strengthens and supports the cell; made of cellulose in plants and peptidoglycan in bacteria. made of mycolic acids and other complex lipids. Mutations that enhance the cell wall's impermeability can reduce drug penetration, further contributing to resistance.