Understanding Antituberculosis Drugs: Mechanisms, Resistance, and Clinical Use

Introduction

Tuberculosis (TB) remains one of the most significant global health challenges, despite advances in medical science and public health. The causative agent, Mycobacterium tuberculosis, is a resilient pathogen that can survive in the human body for years. Antituberculosis agents, the cornerstone of TB treatment, have played a crucial role in controlling the spread and impact of this disease. These agents are vital for curing patients, preventing transmission, and reducing the emergence of drug-resistant strains.

This article provides a comprehensive overview of antituberculosis agents, their mechanisms of action, resistance patterns, and clinical applications. It aims to serve as an authoritative resource for doctors and healthcare professionals seeking to understand the intricacies of TB treatment.

Historical Perspective on Antituberculosis Agents

Before the advent of antituberculosis drugs, TB was a leading cause of death worldwide. The first breakthrough came with the discovery of streptomycin in 1943, which marked the beginning of modern TB therapy. The subsequent development of isoniazid in 1952 and rifampicin in 1963 revolutionized TB treatment, establishing the foundation for the combination therapy that is still used today.

Classification of Antituberculosis Agents

Antituberculosis agents are classified into first-line and second-line drugs based on their efficacy, toxicity, and role in treatment regimens.

First-Line Antituberculosis Agents

First-line drugs are the most effective and are used in the initial phase of TB treatment. They include:

1. Isoniazid (INH)
   • Mechanism of Action: Isoniazid inhibits the synthesis of mycolic acids, essential components of the mycobacterial cell wall.
   • Clinical Use: It is the cornerstone of TB therapy due to its high bactericidal activity against rapidly dividing TB bacilli.
   • Side Effects: Hepatotoxicity, peripheral neuropathy (often prevented by co-administration of pyridoxine), and hypersensitivity reactions.
   • Resistance: Resistance to isoniazid can occur through mutations in the katG gene, which encodes catalase-peroxidase, and in the inhA gene, which is involved in mycolic acid synthesis.
2. Rifampicin (RIF)
   • Mechanism of Action: Rifampicin inhibits bacterial RNA synthesis by binding to the DNA-dependent RNA polymerase.
   • Clinical Use: It is a key bactericidal agent in both active TB and latent TB infections.
   • Side Effects: Hepatotoxicity, gastrointestinal disturbances, and orange discoloration of bodily fluids. Drug interactions are common due to the induction of cytochrome P450 enzymes.
   • Resistance: Resistance to rifampicin typically involves mutations in the rpoB gene, which encodes the RNA polymerase beta subunit.
3. Ethambutol (EMB)
   • Mechanism of Action: Ethambutol inhibits the synthesis of arabinogalactan, a component of the mycobacterial cell wall.
   • Clinical Use: Used primarily to prevent resistance when combined with other TB drugs.
   • Side Effects: Optic neuritis (dose-dependent), leading to visual disturbances and color blindness.
   • Resistance: Resistance arises through mutations in the embB gene, involved in arabinogalactan biosynthesis.
4. Pyrazinamide (PZA)
   • Mechanism of Action: Pyrazinamide is converted to its active form, pyrazinoic acid, which disrupts mycobacterial cell membrane metabolism and transport functions.
   • Clinical Use: Effective against dormant mycobacteria within acidic environments, such as those found in phagolysosomes.
   • Side Effects: Hepatotoxicity, hyperuricemia, and arthralgia.
   • Resistance: Resistance is linked to mutations in the pncA gene, which encodes pyrazinamidase, the enzyme responsible for converting pyrazinamide to its active form.
5. Streptomycin (SM)
   • Mechanism of Action: Streptomycin binds to the 30S ribosomal subunit, inhibiting protein synthesis.
   • Clinical Use: Historically significant as the first effective TB drug, now used mainly for drug-resistant TB.
   • Side Effects: Ototoxicity, nephrotoxicity, and neuromuscular blockade.
   • Resistance: Resistance is associated with mutations in the rpsL and rrs genes, encoding ribosomal proteins and 16S rRNA, respectively.

Second-Line Antituberculosis Agents

Second-line drugs are used when first-line drugs cannot be used due to resistance or intolerance. They include:

1. Fluoroquinolones (e.g., Levofloxacin, Moxifloxacin)
   • Mechanism of Action: Fluoroquinolones inhibit DNA gyrase, preventing DNA replication.
   • Clinical Use: Used in multidrug-resistant TB (MDR-TB) regimens.
   • Side Effects: Tendonitis, tendon rupture, and QT prolongation.
   • Resistance: Resistance develops through mutations in the gyrA and gyrB genes.
2. Injectable Agents (e.g., Amikacin, Capreomycin, Kanamycin)
   • Mechanism of Action: These drugs inhibit protein synthesis by binding to ribosomal RNA.
   • Clinical Use: Essential components of MDR-TB treatment regimens.
   • Side Effects: Ototoxicity, nephrotoxicity, and electrolyte disturbances.
   • Resistance: Resistance mechanisms vary by drug but generally involve ribosomal mutations or enzymatic modification.
3. Ethionamide
   • Mechanism of Action: Ethionamide inhibits mycolic acid synthesis, similar to isoniazid.
   • Clinical Use: Used in MDR-TB and extensively drug-resistant TB (XDR-TB).
   • Side Effects: Gastrointestinal disturbances, hepatotoxicity, and hypothyroidism.
   • Resistance: Resistance is linked to mutations in the ethA gene, involved in drug activation.
4. Cycloserine
   • Mechanism of Action: Cycloserine inhibits cell wall synthesis by blocking the incorporation of D-alanine into peptidoglycan.
   • Clinical Use: Used as a second-line drug in MDR-TB regimens.
   • Side Effects: Neurotoxicity, including seizures, depression, and psychosis.
   • Resistance: Resistance is associated with mutations in the ddl gene, encoding D-alanine ligase.
5. Linezolid
   • Mechanism of Action: Linezolid inhibits protein synthesis by binding to the 50S ribosomal subunit.
   • Clinical Use: Effective against MDR-TB and XDR-TB, especially in cases with extensive lung damage.
   • Side Effects: Bone marrow suppression, peripheral neuropathy, and lactic acidosis.
   • Resistance: Resistance arises through mutations in the 23S rRNA gene.

Mechanisms of Drug Resistance in Tuberculosis

Drug-resistant TB is a major public health concern, complicating treatment and increasing mortality rates. Resistance can be classified as:

• Primary Resistance: When a patient is infected with a strain of M. tuberculosis that is already resistant to one or more drugs.
• Acquired Resistance: When resistance develops during TB treatment due to inadequate therapy, non-adherence, or drug malabsorption.

Mechanisms of Resistance

1. Genetic Mutations: The most common mechanism, where mutations in target genes reduce the efficacy of drugs.
2. Efflux Pumps: Overexpression of efflux pumps in mycobacteria can expel drugs, reducing their intracellular concentration.
3. Enzymatic Inactivation: Some mycobacteria produce enzymes that inactivate drugs, such as aminoglycoside-modifying enzymes for streptomycin resistance.

Clinical Application of Antituberculosis Agents

Treatment of Drug-Sensitive TB

The standard regimen for drug-sensitive TB includes a combination of isoniazid, rifampicin, ethambutol, and pyrazinamide for the initial two months, followed by isoniazid and rifampicin for an additional four months. This regimen has a high success rate when adhered to correctly.

Treatment of Drug-Resistant TB

MDR-TB and XDR-TB require more complex and prolonged treatment regimens, often involving second-line drugs. Treatment can last up to 24 months, with varying success rates. Newer drugs like bedaquiline and delamanid have shown promise in treating resistant TB strains.

Treatment of Latent TB

Latent TB is treated to prevent progression to active disease, especially in high-risk individuals. The preferred regimen is isoniazid for 6-9 months or rifampicin for 4 months. Combination therapy with isoniazid and rifapentine administered weekly for 12 weeks is also effective.

Future Directions in TB Treatment

The emergence of drug-resistant TB strains and the lengthy treatment regimens highlight the need for new antituberculosis agents. Research is ongoing to develop drugs with novel mechanisms of action, shorter treatment durations, and fewer side effects. Potential targets include:

• Cell Wall Biosynthesis: New drugs targeting enzymes involved in mycolic acid and peptidoglycan synthesis are under investigation.
• ATP Synthase: Bedaquiline, a novel drug that targets mycobacterial ATP synthase, is a promising addition to the TB treatment arsenal.
• RNA Polymerase: Drugs targeting different sites on RNA polymerase than rifampicin are being explored to combat rifampicin-resistant strains.

Conclusion

Antituberculosis agents are vital tools in the global fight against TB. Understanding their mechanisms of action, resistance patterns, and clinical applications is essential for healthcare professionals involved in TB management. As research progresses, the hope is to develop more effective and shorter treatment regimens, ultimately reducing the global burden of TB.