All of the following are mechanisms of drug resistance in MDR-TB EXCEPT:

Explanation

## Mechanisms of Drug Resistance in MDR-TB **Key Point:** MDR-TB (resistant to isoniazid and rifampicin) develops through multiple molecular mechanisms affecting drug uptake, activation, and target modification. ### Correct Mechanisms of Resistance | Mechanism | Drug(s) Affected | Molecular Basis | Example | |-----------|-----------------|-----------------|----------| | Altered cell wall permeability | Isoniazid, rifampicin | Mutations in *mmpL5*, *mmpL6*, porins | Reduced drug entry | | Enzymatic inactivation | Rifampicin | Rifampicin-modifying enzymes (ADP-ribosyl transferases) | *arr* gene mutations | | Efflux pump upregulation | Multiple drugs | Overexpression of *efpA*, *mmpL5* | Active drug extrusion | | Target modification | Isoniazid | Mutations in *katG*, *inhA* | Reduced pro-drug activation | ### Why Option 3 is INCORRECT **High-Yield:** Isoniazid is a **pro-drug** that requires activation by mycobacterial catalase-peroxidase (KatG). It does NOT directly bind the ribosomal 30S subunit. Instead: 1. KatG converts isoniazid → isoniazid radical 2. The radical binds **mycolic acid synthesis enzymes** (InhA, KasA) 3. This inhibits cell wall synthesis, not protein synthesis **Warning:** Confusing isoniazid with aminoglycosides (which DO target the 30S ribosome) is a common trap. Isoniazid's mechanism is entirely different — it targets **cell wall synthesis**, not translation. ### Correct Resistance Mechanisms Explained **Option 1 (Altered permeability):** Mutations in porins and mycolic acid synthesis genes reduce drug penetration across the mycobacterial cell wall. **Option 2 (Enzymatic inactivation):** Rifampicin-modifying enzymes phosphorylate or ADP-ribosylate rifampicin, rendering it inactive. This is encoded by *arr* genes. **Option 4 (Efflux pumps):** Upregulation of *mmpL5* and *efpA* actively pumps drugs out of the cell, reducing intracellular concentration below therapeutic levels. **Clinical Pearl:** The most common mechanism of isoniazid resistance is mutation in *katG* (loss of pro-drug activation), not direct ribosomal binding.