Understanding: What is the mechanism of Antituberculosis?

October 6, 2025 •

3 min read

Globally, tuberculosis (TB) remains a leading infectious cause of death, with over 10 million people falling ill each year. A critical aspect of combating this resilient disease is understanding the multifaceted mechanisms of Antituberculosis drugs, which attack Mycobacterium tuberculosis at multiple, essential life processes.

Quick Summary

Antituberculosis drugs employ diverse strategies to kill or inhibit Mycobacterium tuberculosis by targeting vital bacterial functions like cell wall synthesis, RNA production, and metabolism to overcome resilience and prevent resistance.

Key Points

Combination is Key: Effective antituberculosis therapy relies on a combination of drugs with different mechanisms to prevent the rapid development of resistance.
Isoniazid Attacks the Cell Wall: Isoniazid, after activation by the KatG enzyme, inhibits the synthesis of mycolic acids, compromising the integrity of the mycobacterial cell wall.
Rifampin Blocks Genetic Production: Rifampin binds to and inhibits bacterial RNA polymerase, preventing the transcription of RNA and subsequently blocking protein synthesis.
Pyrazinamide Targets Dormant Bacilli: Pyrazinamide is converted to its active form, pyrazinoic acid, which is effective against non-replicating mycobacteria in acidic environments, such as within macrophages.
Ethambutol Increases Permeability: Ethambutol inhibits arabinosyl transferase, disrupting the synthesis of arabinogalactan in the cell wall and increasing its permeability.
Resistance Mechanisms are Diverse: Drug resistance arises from genetic mutations that alter drug targets, impair prodrug activation, or increase efflux pump activity.
Prolonged Treatment is Necessary: The extended duration of TB therapy is required to kill all bacteria, including slow-growing persisters, and to prevent disease relapse.

The First-Line Antituberculosis Drugs

The standard initial treatment for drug-susceptible TB involves four first-line drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. Each drug targets a specific part of the bacterium.

Isoniazid (INH)

Isoniazid kills actively dividing mycobacteria. It is a prodrug activated by a bacterial enzyme, inhibiting the synthesis of mycolic acids, a vital part of the cell wall. Disrupting mycolic acid synthesis weakens the cell wall and kills the cell. Resistance often involves mutations that prevent activation.

Rifampin (RIF)

Rifampin kills bacteria by interfering with RNA production. It binds to bacterial RNA polymerase, blocking the process of creating RNA from DNA. This prevents protein synthesis essential for the bacteria. Rifampin specifically targets bacterial RNA polymerase and not human enzymes. Resistance is commonly caused by mutations that alter the binding site.

Pyrazinamide (PZA)

Pyrazinamide is effective against dormant mycobacteria, particularly in acidic environments. It's a prodrug converted to pyrazinoic acid (POA) by a bacterial enzyme. POA affects multiple targets, potentially interfering with energy production and enzyme activity, disrupting metabolism in dormant states. Resistance often involves mutations affecting its activation.

Ethambutol (EMB)

Ethambutol prevents resistance to other drugs. It inhibits an enzyme crucial for synthesizing arabinogalactan, a cell wall component. Blocking this synthesis disrupts the cell wall structure and increases its permeability. Resistance is linked to mutations in the genes involved in this process.

Why Combination Therapy is Necessary

Using a single drug quickly leads to resistance due to bacterial mutations. Combination therapy uses multiple drugs to provide several benefits:

Synergy: Drugs work together for a greater killing effect.
Targeting Various Bacterial States: Different drugs target bacteria in active, slow-growing, or dormant states.
Killing Resistant Bacteria: If a bacterium is resistant to one drug, the others can kill it.

Mechanisms of Drug Resistance

Drug resistance is a significant issue and can occur through several ways.

Common Mechanisms of Resistance:

Gene Mutations: Changes in genes for drug targets can prevent drug binding.
Prodrug Activation Issues: Mutations in enzymes that activate prodrugs lead to inactive drugs.
Efflux Pumps: Bacteria can pump drugs out of the cell.
Cell Wall Changes: Alterations in the cell wall can make it harder for drugs to enter.

First-Line vs. Second-Line Antituberculosis Drugs


Feature	First-Line Drugs	Second-Line Drugs
Efficacy	More effective for susceptible TB.	Less effective, used for resistant strains.
Toxicity	Lower toxicity.	Higher toxicity.
Cost	Less expensive.	More expensive.
Use Case	Standard treatment for susceptible TB.	Used for resistant TB or intolerance to first-line drugs.
Examples	Isoniazid, Rifampin, Pyrazinamide, Ethambutol.	Fluoroquinolones, Bedaquiline, Linezolid.

The Rationale for Long Treatment Duration

The lengthy treatment for TB, often six months or more, is necessary because of the bacteria's nature and the presence of persister cells.

Drug Tolerance: Some bacteria can survive drug exposure temporarily without genetic resistance, a state called drug tolerance. These slow-growing or non-replicating cells are less affected by drugs targeting active processes.
Bacterial Load: High numbers of bacteria, especially in cavities, require longer treatment to eliminate all cells, including phenotypically resistant ones.
Preventing Relapse: Long treatment ensures all dormant bacteria are killed, preventing the disease from returning.

Conclusion

Antituberculosis drugs work by targeting multiple vital processes in M. tuberculosis. From attacking the cell wall with isoniazid and blocking RNA production with rifampin to affecting dormant bacteria with pyrazinamide, these drugs work together to overcome the bacterium's defenses. Combination therapy and long treatment are essential due to the bacterium's complexity and ability to develop resistance. Understanding these mechanisms is crucial for developing better treatments as drug resistance remains a global challenge.

World Health Organization provides global guidance on TB treatment and prevention.

Frequently Asked Questions

Combination therapy is essential because Mycobacterium tuberculosis can easily develop resistance to a single drug through spontaneous genetic mutations. By using multiple drugs with different mechanisms of action, the chance of a bacterium being resistant to all of them is significantly reduced, ensuring effective treatment and preventing resistance.

A prodrug is an inactive compound that must be metabolized within the body to become an active drug. In the context of TB, isoniazid and pyrazinamide are examples of prodrugs that are converted by bacterial enzymes (katG and pncA, respectively) to their active forms inside the mycobacterium.

Rifampin is designed to selectively bind to the bacterial DNA-dependent RNA polymerase, a key enzyme in transcription. The structure of this enzyme in bacteria is different from its mammalian counterpart, meaning rifampin does not bind to human RNA polymerase, minimizing its toxicity to human cells.

Pyrazinamide is crucial for its ability to target and kill non-replicating or semi-dormant bacilli that other drugs miss. These persister cells, often found in acidic environments like macrophages, are responsible for the extended treatment period. Its inclusion in the regimen allows for a shorter course of therapy.

Ethambutol inhibits arabinosyl transferase, an enzyme necessary for creating the arabinogalactan component of the mycobacterial cell wall. This disruption leads to a compromised cell wall with increased permeability, making the bacterium more vulnerable to other antituberculosis drugs.

Resistance to isoniazid most commonly occurs when the bacterium develops a mutation in the katG gene, which codes for the enzyme that activates isoniazid. Without activation, the drug remains inactive and cannot inhibit mycolic acid synthesis.

Phenotypic resistance, or drug tolerance, refers to the ability of M. tuberculosis to temporarily survive antibiotic exposure without having specific genetic resistance mutations. This often occurs when bacteria enter a slow-growing or non-replicating state, making them less susceptible to drugs that target active cellular processes.

TB treatment is long because the bacteria have a slow growth rate and can exist in different physiological states, including a dormant or 'persister' state that is tolerant to most drugs. The duration is necessary to eradicate all bacterial populations and prevent relapse.