Naringenin as potentiator of norfloxacin efficacy through inhibition of the NorA efflux pump in Staphylococcus aureus.

Bacterial resistance is a major challenge in the treatment of Staphylococcus aureus infections, with efflux mechanisms highlighted as reducing the efficacy of antibiotics. In this study, we investigated the potential of naringenin, a natural flavonoid, as an antibacterial agent and efflux pump inhibitor in S. aureus strains 1199 and 1199B. The studies used minimum inhibitory concentration (MIC) assays, ethidium bromide (EtBr) fluorescence emission enhancement assays, cell membrane permeability assays, and in silico molecular docking and ADME prediction assays. Naringenin showed no relevant antibacterial activity (MIC ≥1024 μg/mL). However, it potentiated the effect of norfloxacin and EtBr, reducing their MICs and increasing the fluorescence emission of EtBr, suggesting a possible inhibition of the NorA efflux pump. Bacterial membrane permeability was not significantly affected. Molecular docking assays indicated that naringenin interacts with the chlorpromazine binding site and has more favorable affinity energy than the chlorpromazine-NorA complex. ADME prediction showed favorable physicochemical properties, good oral absorption, metabolic stability and central nervous system safety. Therefore, naringenin demonstrates the potential to reverse the efficacy of norfloxacin in S. aureus by associating with efflux inhibition through effective interactions with the NorA protein, suggesting its therapeutic potential against bacterial resistance.