Mechanism of Action of Pretomanid
Pretomanid is a nitroimidazooxazine antimycobacterial drug that kills Mycobacterium tuberculosis through dual mechanisms: inhibiting mycolic acid biosynthesis in actively replicating bacteria and acting as a respiratory poison via nitric oxide release in non-replicating bacteria. 1
Primary Mechanisms of Action
Pretomanid's antimycobacterial activity operates through two distinct pathways:
Against Actively Replicating M. tuberculosis:
Against Non-Replicating (Dormant) M. tuberculosis:
Activation Pathway
Pretomanid is a prodrug that requires activation within mycobacterial cells:
- Requires nitro-reduction within the mycobacterial cell
- Activation depends on the deazaflavin-dependent nitroreductase (Ddn)
- Ddn is dependent on the reduced form of cofactor F420
- Reduction of F420 is accomplished by F420-dependent glucose-6-phosphate dehydrogenase (Fgd1) 1
Resistance Mechanisms
Resistance to pretomanid can develop through mutations in several genes:
Five key genes associated with resistance:
These genes encode proteins involved in the bioreductive activation pathway of pretomanid
In vitro frequency of resistance development ranges from 10⁻⁷ to 10⁻⁵ at 2-6 times the MIC 1
Cross-resistance with other compounds in the same class has been observed 1
Clinical Applications
Pretomanid has been approved as part of the BPaL regimen (bedaquiline, pretomanid, and linezolid) for:
- Pulmonary extensively drug-resistant tuberculosis (XDR-TB)
- Treatment-intolerant multidrug-resistant tuberculosis (MDR-TB)
- Non-responsive multidrug-resistant tuberculosis 2, 5
The addition of pretomanid to bedaquiline-containing regimens has demonstrated significant benefits:
- Increases bactericidal activity
- Prevents emergence of bedaquiline resistance
- Shortens treatment duration needed to prevent relapse 6
Pharmacokinetic Considerations
- Primarily metabolized in the liver
- Approximately 90% of the drug is excreted in feces, primarily as metabolites
- Only about 1% is excreted in urine as unchanged pretomanid 1
Important Clinical Considerations
- Pretomanid can interact with drugs metabolized by CYP3A4
- Co-administration with rifampin significantly decreases pretomanid exposure (AUC decreased by 66%)
- Pretomanid is an inhibitor of OAT3 transporters, which may increase concentrations of OAT3 substrate medications 1
- Peripheral neuropathy and increased liver enzymes are reported adverse events 2
Understanding pretomanid's dual mechanism of action explains its effectiveness against both actively replicating and dormant M. tuberculosis, making it a valuable component in novel regimens for drug-resistant tuberculosis.