Nitrofurantoin Resistance Mechanisms in Urinary Tract Infections

Nitrofurantoin remains a first-line agent for uncomplicated urinary tract infections owing to its broad spectrum and multifaceted mode of action. As a prodrug, it undergoes intracellular reduction by bacterial nitroreductases, generating reactive intermediates that damage DNA, ribosomal proteins and key metabolic pathways. Resistance has typically evolved through loss-of-function mutations in chromosomal nitroreductase genes (nfsA and nfsB) or in the associated ribE gene, reducing prodrug activation. Reduced drug uptake via altered porin channels and increased efflux through plasmid-associated pumps (most notably oqxAB under the control of oqxR) further diminish intracellular concentrations. Large-scale genomic deletions adjacent to insertion sequences can excise nitroreductase loci, giving rise to heteroresistant subpopulations that evade standard susceptibility testing. Recent reports also describe mutations in extended-spectrum β-lactamases that acquire the ability to hydrolyse nitrofurantoin. The need for multiple stepwise genetic changes to confer high-level resistance has historically limited its spread, yet surveillance indicates a gradual rise in resistant strains worldwide. Continued stewardship and mechanistic insight are vital to preserve nitrofurantoin’s clinical utility and guide combination strategies against multidrug-resistant uropathogens.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Nitrofurantoin Resistance Mechanisms in Urinary Tract Infections publication trend

The graph below shows the total number of articles in nitrofurantoin resistance mechanisms in urinary tract infections across all publications each year (not limited to Nature Index journals).

Technical terms

Nitroreductase: Enzyme (commonly NfsA and NfsB) that reduces nitrofurantoin to reactive intermediates within bacterial cells.

Porin: A protein channel in the outer membrane of Gram-negative bacteria that allows small molecules, including antibiotics, to enter.

Efflux pump: Membrane protein complex that actively exports antimicrobial agents from bacterial cells, lowering intracellular drug levels.

Insertion sequence (IS element): A short DNA segment capable of moving within the genome, which can disrupt or delete neighbouring genes upon integration.

Heteroresistance: The coexistence of bacterial subpopulations with differing antibiotic susceptibilities within a single isolate.

Minimum inhibitory concentration (MIC): The lowest concentration of an antibiotic that prevents visible growth of a bacterial culture.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can damage cellular components, generated during nitrofurantoin activation.

References

1. Role of Old Antibiotics in the Era of Antibiotic Resistance. Highlighted Nitrofurantoin for the Treatment of Lower Urinary Tract Infections. Antibiotics (2014).
2. Genomic insights into nitrofurantoin resistance mechanisms and epidemiology in clinical Enterobacteriaceae. Future Science OA (2018).
3. Alterations in chromosomal genes nfsA, nfsB, and ribE are associated with nitrofurantoin resistance in Escherichia coli from the United Kingdom. Microbial Genomics (2021).
4. IS1-related large-scale deletion of chromosomal regions harbouring the oxygen-insensitive nitroreductase gene nfsB causes nitrofurantoin heteroresistance in Escherichia coli. Microbial Genomics (2023).
5. High-level nitrofurantoin resistance in a clinical isolate of Klebsiella pneumoniae: a comparative genomics and metabolomics analysis. mSystems (2023).
6. The Amino Acid Changes T55A, A273P and R277C in the Beta-Lactamase CTX-M-14 Render E. coli Resistant to the Antibiotic Nitrofurantoin, a First-Line Treatment of Urinary Tract Infections. Microorganisms (2020).
7. Insights into durability against resistance from the antibiotic nitrofurantoin. npj Antimicrobials and Resistance (2024).