Discuss the first-line antimycobacterial drugs with special reference to their mechanism of action, side effects and development of resistance.

First-Line Antimycobacterial Drugs: A Detailed Overview

The standard first-line treatment regimen for TB typically involves a combination of all four drugs for an initial intensive phase, followed by a continuation phase with Isoniazid and Rifampicin. This approach maximizes efficacy and minimizes the risk of resistance development.

1. Isoniazid (INH)

• Mechanism of Action: Isoniazid is a prodrug activated by the bacterial catalase-peroxidase enzyme KatG. The activated form inhibits the synthesis of mycolic acids, essential components of the mycobacterial cell wall. Specifically, it inhibits InhA, an enoyl-acyl carrier protein reductase involved in mycolic acid biosynthesis.
• Side Effects: Common side effects include peripheral neuropathy (due to pyridoxine deficiency), hepatotoxicity, and gastrointestinal disturbances. Prophylactic pyridoxine supplementation is often recommended.
• Resistance: Resistance primarily develops through mutations in the *katG* gene (reducing INH activation) or the *inhA* gene (altering the target enzyme).

2. Rifampicin (RIF)

• Mechanism of Action: Rifampicin inhibits bacterial DNA-dependent RNA polymerase, specifically binding to the β-subunit and preventing RNA transcription. This effectively halts bacterial protein synthesis.
• Side Effects: Common side effects include hepatotoxicity, orange discoloration of body fluids (urine, tears, sweat), and gastrointestinal upset. It's a potent inducer of cytochrome P450 enzymes, leading to drug interactions.
• Resistance: Resistance is commonly caused by mutations in the *rpoB* gene, encoding the β-subunit of RNA polymerase. These mutations alter the drug-binding site, reducing Rifampicin’s affinity.

3. Pyrazinamide (PZA)

• Mechanism of Action: Pyrazinamide is a prodrug converted to pyrazinoic acid by the mycobacterial enzyme pyrazinamidase. The exact mechanism of action is still debated, but it's believed to disrupt membrane transport functions and inhibit fatty acid synthesis I. It is most effective against semi-dormant bacteria in acidic environments.
• Side Effects: Common side effects include hepatotoxicity and hyperuricemia (leading to gout).
• Resistance: Resistance often arises from mutations in the *pncA* gene, encoding pyrazinamidase, preventing the conversion of pyrazinamide to its active form.

4. Ethambutol (EMB)

• Mechanism of Action: Ethambutol inhibits arabinosyl transferases (EmbA, EmbB, and EmbC), enzymes involved in the synthesis of arabinogalactan, a crucial component of the mycobacterial cell wall.
• Side Effects: The most significant side effect is optic neuritis, leading to decreased visual acuity and color vision. Regular monitoring of visual function is essential.
• Resistance: Resistance typically develops through mutations in the *embB* gene, altering the target enzyme and reducing drug binding.

The following table summarizes the key features of each drug:

Drug	Mechanism of Action	Common Side Effects	Resistance Mechanism
Isoniazid	Inhibits mycolic acid synthesis	Peripheral neuropathy, Hepatotoxicity	Mutations in *katG* or *inhA*
Rifampicin	Inhibits RNA polymerase	Hepatotoxicity, Orange body fluids	Mutations in *rpoB*
Pyrazinamide	Disrupts membrane transport & fatty acid synthesis I	Hepatotoxicity, Hyperuricemia	Mutations in *pncA*
Ethambutol	Inhibits arabinosyl transferases	Optic neuritis	Mutations in *embB*

The development of resistance is a significant challenge in TB control. Factors contributing to resistance include incomplete treatment, poor adherence to medication, and the emergence of pre-existing resistant strains. Rapid diagnostic tests, such as GeneXpert MTB/RIF assay, are crucial for early detection of drug resistance and guiding appropriate treatment regimens.