Antimicrobial resistance is one of the most pressing global health challenges, with many antibiotics succumbing to resistance within a decade of clinical use. However, nitrofurantoin, a staple for treating urinary tract infections (UTIs) since the 1950s, counters this trend. Despite its widespread use, resistance to nitrofurantoin remains exceptionally low. A Manchester-based team, led by Dr Danna Gifford (EIGen) and involving Dr Mato Lagator (EIGen) and Professor Tim Felton (DIIRM and MFT), has recently explored the factors behind this durability and what it can teach us about developing new treatments.

Why does Nitrofurantoin work so well? Several factors contribute to its enduring effectiveness:

• Targeted to the site of infection: Nitrofurantoin rapidly achieves high concentrations in the urinary tract, its primary site of action, minimising opportunities for resistant mutants to emerge in the microbiome.
• Multifaceted mechanism of action: By disrupting multiple bacterial processes, including protein and DNA synthesis, nitrofurantoin makes it harder for bacteria to develop resistance.
• Requirement for multiple mutations for full resistance: Clinical resistance requires multiple mutations in specific genes (nfsA and nfsB), a rarity in evolutionary terms.
• Limited horizontal gene transfer: Unlike many antibiotics, nitrofurantoin lacks an extensive reservoir of resistance genes, reducing the risk of widespread resistance through gene sharing.

Nitrofurantoin’s success can serve as a blueprint for designing new antibiotics that are robust against resistance. By combining targeted delivery, multifactorial action, and evolutionary barriers to resistance, future drugs can emulate nitrofurantoin’s longevity.

However, despite its strengths, nitrofurantoin isn’t invulnerable. The team also identified several risks to its ongoing efficacy. Emerging resistance linked to efflux pumps and mutation-prone “mutator” strains in clinical isolates highlights the importance of responsible usage and continued monitoring.

This perspective highlights the importance of patient adherence, cautious prophylactic use, and vigilant surveillance to safeguard nitrofurantoin’s continued efficacy. Additionally, understanding and applying the principles underlying its durability could guide the development of future antibiotics, providing a strategic approach to combat antimicrobial resistance.

Read more at npj Antimicrobials and Resistance