Anti-quorum Sensing Activity of quercetin in Combination with imipenem and ciprofloxacin against Pseudomonas aeruginosa

Background and Objectives: The inhibition of quorum sensing (QS) is considered as a novel strategy for the development of antipathogenic agents and management of nosocomial infections caused by Pseudomonas aeruginosa.The present study aimed to investigate the anti-quorum sensing activity of sub-MIC concentrations of quercetin (Q), imipenem (IPM) and ciprofloxacin (CIP)alone and in combination against P. aeruginosa. Materials and Methods: We determined the MIC and synergistic activity of Q, IPM and CIP against P. aeruginosaPAO1. The effect of sub-MIC (1/4 and 1/16 MIC) concentrations of Q, IPM and CIP alone and in combination on QS related virulence factors and expression of lasI and lasRgenes were also determined. Results: The addition of Q decreased the MIC of IPM and CIP and there was additive effect from these combinations. Quercetin did not show significant effects on cell growthat concentrations of 1/4 and 1/16 MIC. However, sub-MIC concentrations (1/4 and 1/16 MIC) of Q in combination with IPM or CIP showed the significant reduction in QS dependent phenotypes like violacein production,swarming and twitching motilities, biofilm formation, alginate and pyocyanin production and sensivity toH2O2 in a concentration dependent manner (P<0.001). The combination of Qwith IPM or CIPat the concentrations of 1/4 MICshowed the greatest reductionin the expression levels of lasIcompared with untreated control (P<0.001).We also carried out molecular docking for understanding the interactions of quercetin with the LasR receptor.The docking results suggested that quercetin has potential to inhibit the LasR protein. Conclusion: Considering the beneficial biological effects of quercetin and its inhibitory effects on QS related virulence traits, the combination of this natural compound with imipenem or ciprofloxacin may be used as an effective approach to the management of multidrug resistant infections of P. aeruginosa.