Mechanism of Action of Nitrofurantoin
Nitrofurantoin is a prodrug that requires activation by bacterial nitroreductases, after which it inhibits multiple bacterial targets including DNA, RNA, cell wall, and protein synthesis, resulting in bactericidal activity against uropathogens. 1, 2
Activation Process
- Nitrofurantoin must be enzymatically activated by bacterial nitroreductases before it can exert its antimicrobial effects. 1
- The activation process requires reducing equivalents (electron donors) to convert the prodrug into its active metabolites. 1
- This metabolic activation is critical—stationary-phase bacteria with insufficient reducing equivalents show resistance to nitrofurantoin until metabolites like glucose are supplemented to restore cellular metabolism. 1
Multi-Target Bactericidal Activity
Once activated, nitrofurantoin demonstrates broad-spectrum bactericidal effects through simultaneous inhibition of multiple bacterial processes:
- DNA synthesis inhibition is one of the primary mechanisms of bacterial killing. 1, 2
- RNA synthesis inhibition occurs concurrently, disrupting bacterial transcription. 1, 2
- Cell wall protein synthesis inhibition compromises bacterial structural integrity. 1, 2
- Protein synthesis inhibition prevents essential bacterial enzyme production. 1, 2
Clinical Implications of the Mechanism
Why Nitrofurantoin Works Well for UTIs
- The multi-target mechanism explains why nitrofurantoin has maintained excellent activity against E. coli for over 60 years despite widespread use, as simultaneous resistance to all targets is unlikely to develop. 3, 4
- The bactericidal (killing) rather than bacteriostatic (growth-inhibiting) properties make it highly effective for uncomplicated UTIs, with clinical cure rates of 88-93%. 5
Critical Limitation: Requires Active Bacterial Metabolism
- Nitrofurantoin requires metabolically active bacteria with sufficient reducing equivalents for activation, which explains why it only works in the urinary tract where high drug concentrations are achieved. 1
- This metabolic requirement is why nitrofurantoin is contraindicated for pyelonephritis or systemic infections—it does not achieve adequate tissue concentrations outside the urinary tract to maintain bactericidal activity. 6, 7
- The drug is also contraindicated when creatinine clearance is <60 mL/min, as inadequate urinary drug concentrations prevent sufficient activation and bactericidal activity while increasing toxicity risk. 5
Generalizability to Nitrofuran Class
- This activation-dependent mechanism applies broadly to the nitrofuran antibiotic class, including nitrofurazone, suggesting that metabolite availability is a universal requirement for this drug family. 1