Antimicrobial effects of nifuratel against Staphylococcus epidermidis by targeting proton motive force

The increasing antimicrobial resistance of Staphylococcus epidermidis , a leading opportunistic pathogen causing device‑related and nosocomial infections, underscores an urgent need for novel anti‑staphylococcal agents. Nifuratel, a nitrofuran derivative currently used for urogenital tract infections, represents a promising candidate for drug repurposing. In this study, nifuratel showed minimal inhibitory concentrations (MICs) ranging from 0.5 to 2 μg/mL against S. epidermidis , and at 1 μg/mL in Mueller‑Hinton broth reduced the growth turbidity of RP62A and ATCC 12228. At 2×MIC, nifuratel reduced viable counts of S. epidermidis to the detection limit within 12 h. No significant resistance was observed after 15 serial passages at subinhibitory concentrations, and the single‑step induction assay also indicated extremely low resistance potential by nifuratel. Nifuratel exhibited a post‑antibiotic effect similar to ciprofloxacin and showed synergistic or partially synergistic effects with oxacillin or gentamicin. Moreover, nifuratel significantly reduced the fluorescence of the proton motive force ‑related probes DiSC3(5) and BCECF‑AM. In vivo , nifuratel significantly reduced bacterial load and inflammatory exudate in abscesses and wounds. Pathological staining further confirmed reduced inflammatory cell infiltration and accelerated wound healing. Collectively, nifuratel exerts potent bactericidal activity against S. epidermidis by disrupting the transmembrane potential and transmembrane proton gradient of the proton motive force.