From the Guidelines
Pyrazinamide is bactericidal for M. tuberculosis in an acid environment, and its mechanism of action involves disrupting membrane energetics and inhibiting multiple cellular processes, including membrane transport and energy production, particularly in semi-dormant bacilli in acidic environments, such as those found within macrophages and areas of acute inflammation. The drug is active against organisms in macrophages, presumably because of the acid environment within the cell, as noted in the study published in the American Journal of Respiratory and Critical Care Medicine 1. At a pH of 5.5, the minimal inhibitory concentration of pyrazinamide for M. tuberculosis is 20 mg/ml, and absorption from the gastrointestinal tract is nearly complete, with peak serum concentrations of 30–50 mg/ml occurring approximately 2 h after ingestion with doses of 20–25 mg/kg, as reported in the same study 1. Some key points about pyrazinamide's mechanism of action and properties include:
- The drug is particularly effective against semi-dormant bacilli in acidic environments
- It disrupts membrane energetics and inhibits multiple cellular processes, including membrane transport and energy production
- Pyrazinamide is active against organisms in macrophages, presumably because of the acid environment within the cell
- The minimal inhibitory concentration of pyrazinamide for M. tuberculosis is 20 mg/ml at a pH of 5.5, as noted in the study 1. The unique ability of pyrazinamide to kill persistent organisms in acidic environments makes it an essential component of first-line tuberculosis treatment regimens, despite having relatively weak bactericidal activity against actively growing bacteria compared to other antituberculous drugs, as described in the study published in the American Journal of Respiratory and Critical Care Medicine 1.
From the Research
Mechanism of Action of Pyrazinamide
The mechanism of action (MOA) of pyrazinamide involves the inhibition of fatty acid synthetase I (FASI) in Mycobacterium tuberculosis.
- Pyrazinamide is a pro-drug that is converted to pyrazinoic acid (POA), which is the active form of the drug 2.
- The eukaryotic-like FASI enzyme is responsible for the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA, and pyrazinamide inhibits this enzyme, leading to the disruption of fatty acid synthesis in M. tuberculosis 2, 3.
- The inhibition of FASI by pyrazinamide is correlated with its susceptibility in M. tuberculosis, suggesting that FASI is a primary target of action for pyrazinamide 2.
- However, some studies have suggested that pyrazinoic acid may not directly inhibit purified mycobacterial FAS-I, and that the inhibition of fatty acid synthesis may be an indirect effect of the drug 4.
Key Findings
- Pyrazinamide is active against M. tuberculosis, and its addition to the drug regimen is essential for shortening the treatment duration to six months 2, 5.
- The MOA of pyrazinamide involves the inhibition of FASI, which is a critical enzyme for fatty acid synthesis in M. tuberculosis 2, 3.
- The inhibition of FASI by pyrazinamide is specific to M. tuberculosis, and the drug has a broader range of anti-mycobacterial activity when used in combination with other drugs 5, 6.