Potentiation of Ciprofloxacin Activity by Chalcones by Modulating Efflux Pump and Biofilm Regulatory Gene in Staphylococcus Aureus

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Objective: Natural and synthetic compounds with dual activity to inhibit efflux pumps and biofilm production in Staphylococcus aureus (S. aureus) were investigated in this study. Chalcones emerged as potential compounds with the possibility to inhibit efflux pump and biofilm production at once. Methods: We performed pre-clinical screenings of different chalcones-ciprofloxacin combinations with a NorA overexpressing S. aureus strain. Chalcones inhibition of the NorA efflux pump and Agr gene expression, a major regulator of biofilm formation, were tested. In silico modeling was also used to confirm the dual inhibitory activity of chalcones. Results: Chalcones effectively modulated the action of ciprofloxacin by reducing the MIC by 2-8 fold and improving the time kill study, also inhibiting the NorA efflux pump and suppressing Agr gene expression, resulting in increased antibacterial activity and decreased biofilm formation. Conclusion: The present research brings to the limelight chalcones as dual-function inhibitors aiming at efflux-based antibiotic resistance and biofilm formation in S. aureus with a potential strategy to repress drug-resistant infections.