From the Guidelines
Pyrazinamide's mechanism of action involves interfering with mycobacterial fatty acid synthase through its conversion to pyrazinoic acid, a process that is crucial for its effectiveness against M. tuberculosis. This process is supported by a study published in the American Journal of Respiratory and Critical Care Medicine in 2019 1. The study highlights that pyrazinamide is a prodrug that is converted in vivo into pyrazinoic acid, which then interferes with mycobacterial fatty acid synthase. Some key points about pyrazinamide's mechanism of action and use include:
- Pyrazinamide is a nicotinamide analog that has demonstrated effectiveness against M. tuberculosis, making it a crucial component of standard regimens for treatment of drug-susceptible TB and regimens for MDR-TB 1.
- The effectiveness of pyrazinamide is reduced in the setting of pncA gene mutations, underscoring the importance of documenting drug susceptibility to pyrazinamide by WGS, molecular tests, or traditional DST, if the drug is to be included as part of a regimen for MDR-TB 1.
- Pyrazinamide resistance is highly associated with rifampin resistance, as shown by recent population-based studies conducted as part of multicountry surveillance activities 1. Overall, pyrazinamide's unique mechanism of action makes it a valuable component of TB treatment regimens, particularly in the intensive phase of treatment.
From the FDA Drug Label
The mechanism of action is unknown. The MoA of pyrazinamide is unknown. 2
From the Research
Mechanism of Action of Pyrazinamide
The mechanism of action of pyrazinamide (PZA) involves several key steps and targets:
- PZA is a pro-drug that is converted to its active form, pyrazinoic acid (POA), by the nicotinamidase PncA 3
- POA is then excreted by an unknown efflux pump and, at acidic conditions, is protonated to HPOA, which is reabsorbed into the cell where it causes cellular damage 3
- PZA/POA has several different targets, interfering with diverse biochemical pathways, especially in the NAD(+) and energy metabolism 3
- One of the primary targets of PZA is the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis, which is involved in the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA 4
- PZA also disrupts membrane energetics and inhibits membrane transport function in Mycobacterium tuberculosis, with its preferential activity against old non-replicating bacilli correlating with their low membrane potential 5
Key Findings
- The mode of action of PZA remains complex and not fully understood, with multiple targets and mechanisms involved 3
- PZA resistance depends on the interplay of many different enzyme targets and transport mechanisms, rather than just a defective pyrazinamidase 3
- The importance of uncovering the mechanisms of action of PZA in mycobacteria is highlighted, as it may allow for the development of new drugs to shorten therapy against M. tuberculosis and provide more options for treatment against M. bovis, M. avium, and drug-resistant M. tuberculosis 4, 3