Pharmacological Classification of Anti-Tuberculosis Drug Classification

Anti-tuberculosis drugs are primarily classified into two groups based on their efficacy and use: first-line and second-line drugs.

First-Line Drugs

These are the most effective and least toxic drugs used to treat tuberculosis. They are the cornerstone of the standard treatment regimen.

Isoniazid (H):
A potent drug that targets the synthesis of the mycobacterial cell wall.
First-Line Anti-Tuberculosis Drugs
1. Isoniazid (INH)
Maximum and Minimum Dosage:
- Adults: The typical daily dose is 5 mg/kg, with a maximum dose of 300 mg/day. For intermittent (directly observed therapy or DOT) regimens, the dosage can be up to 15 mg/kg, with a maximum of 900 mg, administered two to three times per week.
- Children: The daily dosage is higher, ranging from 10 to 15 mg/kg, with a maximum of 300 mg/day.
Mechanism of Action (MoA): Isoniazid is a prodrug that must be activated by the bacterial enzyme KatG (catalase-peroxidase). Once activated, the drug inhibits the synthesis of mycolic acids, which are essential components of the cell wall of Mycobacterium tuberculosis. This inhibition occurs by forming a covalent adduct with the NAD cofactor, which then acts as a potent inhibitor of InhA, a key enzyme in mycolic acid synthesis.
Chemical Structure: Isoniazid is chemically known as isonicotinic acid hydrazide. Its molecular formula is C6H7N3O.
Rifampin (R):
A broad-spectrum antibiotic that inhibits RNA synthesis.
Maximum and Minimum Dosage:
Adults: The standard daily dosage is 10 mg/kg, with a maximum of 600 mg/day.
Children: Doses typically range from 10 to 20 mg/kg/day, with a maximum of 600 mg/day.
Mechanism of Action (MoA): Rifampin is a potent bactericidal antibiotic. It acts by inhibiting bacterial DNA-dependent RNA polymerase. By binding to this enzyme, it prevents the initiation of transcription, thereby blocking the synthesis of messenger RNA and ultimately halting protein production in the TB bacteria. It does not affect human RNA polymerase.
Chemical Structure: Rifampin has a complex structure. Its molecular formula is C43H58N4O12
Pyrazinamide (Z):
This drug is effective in an acidic environment and helps eliminate semi-dormant bacilli.
Maximum and Minimum Dosage:
Adults and Children: The daily dose is generally 15 to 30 mg/kg, with a maximum of 2000 mg (2 g) per day. For twice-weekly regimens, the dose is 50 to 70 mg/kg, with a maximum of 4000 mg (4 g) per dose.
Mechanism of Action (MoA): Pyrazinamide is a prodrug that requires activation by the bacterial enzyme pyrazinamidase. This enzyme converts pyrazinamide into its active form, pyrazinoic acid. Pyrazinoic acid then accumulates inside the macrophage, where the TB bacilli often reside in an acidic environment. The drug’s active form disrupts membrane function and energy metabolism in the mycobacteria, effectively killing the bacteria in this specific, low-pH setting.
Chemical Structure: Pyrazinamide has the chemical formula C5H5N3O.
Ethambutol (E):
A bacteriostatic drug that prevents the growth of TB bacilli and helps prevent the emergence of resistance.
Maximum and Minimum Dosage:
Initial Treatment: The daily dose for initial treatment is 15 to 25 mg/kg, with a maximum of 2.5 g.
Retreatment: For patients with prior TB treatment, the dose is often 25 mg/kg/day for the first 60 days, then reduced to 15 mg/kg/day.
Intermittent Regimens: Doses can be as high as 50 mg/kg two or three times per week.
Mechanism of Action (MoA): Ethambutol is a bacteriostatic drug, meaning it prevents the growth of bacteria rather than killing them outright. It inhibits the enzyme arabinosyl transferase, which is critical for the synthesis of arabinogalactan, a key component of the mycobacterial cell wall. This action disrupts the formation of the cell wall, making the bacteria unable to multiply.
Chemical Structure: Ethambutol’s molecular formula is C10H24N2O2

Second-Line Drugs

These drugs are used for cases of drug-resistant tuberculosis (MDR-TB and XDR-TB) or when a patient cannot tolerate first-line drugs due to side effects. They are generally less effective and have higher toxicity. Examples include:

Second-line anti-tuberculosis drugs are used primarily for cases of drug-resistant TB or when a patient cannot tolerate first-line drugs. Their mechanisms of action are more varied and often target different cellular processes than the first-line agents.

1. Fluoroquinolones (e.g., Moxifloxacin, Levofloxacin)

Mechanism of Action:Fluoroquinolones are bactericidal antibiotics that work by inhibiting bacterial DNA synthesis. Specifically, they target and inhibit two essential enzymes:
1. DNA gyrase: This enzyme is responsible for unwinding DNA strands to allow replication and transcription. By binding to DNA gyrase, fluoroquinolones prevent this unwinding, leading to DNA damage.
2. Topoisomerase IV: This enzyme separates the duplicated bacterial chromosomes before cell division. Its inhibition by fluoroquinolones prevents the bacteria from replicating and multiplying.
This dual mechanism of action is distinct from first-line drugs like isoniazid and rifampin, which makes fluoroquinolones effective against multi-drug resistant (MDR) strains of M. tuberculosis.

2. Aminoglycosides (e.g., Amikacin, Streptomycin)

Mechanism of Action:Aminoglycosides are a class of injectable antibiotics that work by inhibiting bacterial protein synthesis. Their primary target is the 30S ribosomal subunit.
- Binding to the 30S Subunit: The drug binds irreversibly to the 30S ribosomal subunit, which is a critical component of the bacterial ribosome.
- mRNA Misreading: This binding causes a conformational change in the ribosome, leading to a misreading of the genetic code from messenger RNA (mRNA).
- Production of Faulty Proteins: The misreading results in the incorporation of incorrect amino acids into the growing protein chain, leading to the production of non-functional or toxic proteins. These defective proteins disrupt the bacterium’s metabolism and essential cellular functions, ultimately leading to cell death.

3. Diarylquinolines (e.g., Bedaquiline)

Mechanism of Action:Bedaquiline is a novel drug with a unique mechanism that targets the energy production system of M. tuberculosis.
- Inhibition of ATP Synthase: Bedaquiline specifically inhibits adenosine triphosphate (ATP) synthase, an enzyme essential for generating ATP.
- Energy Depletion: ATP synthase is like a rotary motor that produces energy for the bacterium to live and replicate. By blocking this enzyme, Bedaquiline effectively starves the bacterium of energy, leading to a rapid and potent bactericidal effect, even against dormant or non-replicating bacteria that may be resistant to other drugs.