Synergistic Interaction Between Nitrofurantoin and Dequalinium Provides a Promising Approach to Treating UTIs caused by Antibiotic-Resistant Klebsiella pneumoniae

Nitrofurantoin, a common first-line treatment for urinary tract infections (UTIs), remains effective against most uropathogens; yet, resistance among Klebsiella spp. persists. Researchers explored synergistic drug combinations to boost treatment efficacy against antibiotic-resistant Klebsiella pneumoniae. High-throughput screening yielded six small molecules that showed 50% synergy when paired with nitrofurantoin and two that did so with ciprofloxacin.

The three most promising candidates were subsequently tested against both nitrofurantoin-sensitive and resistant clinical strains of K. pneumoniae. The combination of nitrofurantoin and dequalinium emerged as particularly effective, showing strong synergy in 68% of susceptible E. coli strains and an impressive 94% of resistant K. pneumoniae strains.

This synergistic effect stemmed from nitrofurantoin inhibiting the citric acid cycle and dequalinium blocking the F1-ATPase, leading to a substantial drop in ATP levels compared to either drug alone. Crucially, this reduction in ATP did not lead to increased persister cell formation, and dequalinium alone proved more effective at decreasing persister cell populations than nitrofurantoin.

However, nitrofurantoin generates a reactive intermediate with unknown metabolic targets. Metabolomic analysis revealed that nitrofurantoin alters key enzymes like aconitase and isocitrate dehydrogenase, which are vital in the citric acid cycle. These findings suggest that simultaneously targeting bacterial metabolism through the combined action of nitrofurantoin and dequalinium could be a promising approach for treating UTIs caused by antibiotic-resistant Klebsiella pneumoniae.