What is the mechanism of action of anti-tuberculosis (TB) drugs?

Mechanism of Action of Anti-Tuberculosis Drugs

Anti-TB drugs target distinct bacterial processes: isoniazid (INH) and rifampin (RIF) kill rapidly multiplying bacilli through inhibition of mycolic acid synthesis and RNA polymerase respectively, while pyrazinamide (PZA) sterilizes persistent organisms in acidic environments, and ethambutol (EMB) prevents resistance by blocking cell wall synthesis. 1

First-Line Anti-TB Drugs

Isoniazid (INH)

• Possesses the most potent early bactericidal activity against rapidly multiplying M. tuberculosis, rapidly decreasing infectiousness during initial therapy 1
• Targets mycolic acid synthesis in the bacterial cell wall, though the provided evidence does not detail the specific molecular mechanism 2
• Most effective against the largest subpopulation of extracellular bacilli residing in cavities 1
• Has considerable ability to prevent emergence of drug resistance when combined with another agent 1
• Resistance mutations occur at a frequency of approximately 10^-6 1

Rifampin (RIF)

• Inhibits DNA-dependent RNA polymerase activity in susceptible M. tuberculosis, specifically interacting with bacterial RNA polymerase without affecting the mammalian enzyme 3
• Demonstrates the greatest sterilizing activity that persists throughout the entire course of therapy, killing bacilli in slowly growing and dormant subpopulations 1
• Follows INH, EMB, and streptomycin in early bactericidal activity during initial treatment 1
• Resistance mutations occur at the lowest frequency of 10^-8, making it highly effective in preventing drug resistance when combined with other agents 1
• Undergoes enterohepatic circulation and deacetylation to 25-desacetyl-rifampin, which retains microbiological activity 3

Pyrazinamide (PZA)

• Bactericidal for M. tuberculosis specifically in acidic environments (pH 5.5), making it active against organisms within macrophages 1
• Has weak early bactericidal activity during the first 2 weeks of treatment 1
• Demonstrates significant sterilizing activity second only to rifampin, but this activity is limited to the initial 2 months when given in RIF-containing regimens 1
• Poor ability to prevent emergence of drug resistance, therefore should never be used with only one other agent when treating active tuberculosis 1
• In MDR-TB regimens where RIF is ineffective, PZA may be included for the full treatment course if the isolate remains susceptible 1

Ethambutol (EMB)

• Blocks cell wall synthesis, though the specific molecular target is not detailed in the provided evidence 2
• Ranks third in early bactericidal activity, following INH and preceding RIF and streptomycin 1
• Effective in preventing emergence of drug resistance when combined with other agents 1
• Resistance mutations occur at a frequency of 10^-5 1
• Can be omitted in the initial phase for patients with low risk of isoniazid resistance 4

Second-Line and Alternative Agents

Rifabutin

• Same mechanism of action as rifampin (inhibition of DNA-dependent RNA polymerase), with most rifampin-resistant strains also resistant to rifabutin 1
• Major advantage is longer serum half-life and reduced hepatic induction of microsomal metabolism compared to rifampin 1
• Extensively metabolized in the liver and intestinal wall, with only 8% excreted unchanged in urine 1

Cycloserine

• Inhibits cell wall synthesis in susceptible gram-positive and gram-negative bacteria, including M. tuberculosis 5
• Readily absorbed from the gastrointestinal tract with peak blood levels at 4-8 hours 5
• Approximately 65% recovered unchanged in urine within 72 hours, with remaining 35% metabolized to unknown substances 5

Fluoroquinolones

• Target DNA/RNA synthesis through mechanisms distinct from first-line agents 2, 6
• Demonstrate both early bactericidal and sterilizing activities in clinical trials 1
• Levofloxacin often preferred over moxifloxacin due to lower cardiotoxicity potential 7

Newer Agents (Bedaquiline, Delamanid, Pretomanid)

• Target novel pathways including ATP synthesis (bedaquiline) and cell wall biosynthesis through different mechanisms than traditional agents 6, 8
• Particularly valuable against MDR and XDR strains due to lack of cross-resistance with first-line drugs 9, 6

Three Bacterial Subpopulations and Drug Activity

Rapidly Growing Extracellular Bacilli

• Largest subpopulation residing mainly in lung cavities 1
• Most likely to harbor organisms with random drug resistance mutations due to population size 1
• Targeted primarily by INH with its potent early bactericidal activity, followed by EMB, RIF, and streptomycin 1
• Eliminated early in effective therapy, with approximately 80% of patients clearing live bacilli from sputum within 2 months 1

Slowly Growing Bacilli in Acidic Environments

• Located in areas of necrosis where acidic pH prevails 1
• Specifically targeted by PZA due to its unique activity in acidic environments 1
• Account for treatment failures and relapses when therapy duration is inadequate 1

Dormant Bacilli with Intermittent Growth

• Characterized by spurts of growth interspersed with dormancy periods 1
• Require drugs with sterilizing activity (RIF and PZA) to prevent relapse 1
• Essential target for achieving short-course (6-month) regimens 1

Critical Principles for Combination Therapy

Multiple drugs must always be used simultaneously because monotherapy inevitably leads to treatment failure and drug resistance, as demonstrated historically with streptomycin 1

• The probability of concurrent resistance mutations to both INH and RIF is 10^-14, making simultaneous resistance in untreated patients highly unlikely 1
• Both INH and RIF have considerable ability to prevent resistance emergence when given with another drug 1
• EMB and streptomycin are also effective in preventing resistance, while PZA is poor in this regard 1

Common Pitfalls

• Never use PZA with only one other agent due to its poor ability to prevent drug resistance 1
• Rifampin interacts with numerous medications including oral contraceptives, anticoagulants, and antiretroviral drugs, requiring careful medication review 1, 10
• Resistance can emerge rapidly as single-step mutations, necessitating susceptibility testing if cultures remain positive 3
• The sterilizing activity of PZA is limited to the first 2 months in RIF-containing regimens, though it may contribute throughout treatment in MDR-TB regimens 1