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Background: The increased resistance of bacterial pathogens to fluoroquinolones (FQs), such as norfloxacin and ciprofloxacin, supports the need to develop new antibacterial drugs and combination therapies using conventional antibiotics. The LuxS/AI-2 quorum sensing (QS) system can regulate the complex group behaviour of Streptococcus suis and impact its susceptibility to FQs.Objectives: We investigated the combination of paeoniflorin and norfloxacin as a novel and effective strategy against FQ-resistant S. suis.Methods: FIC, AI-2 activity assay, real-time RT-PCR and biofilm inhibition assays were performed to investigate the in vitro effect of paeoniflorin combined with norfloxacin. Mouse protection and mouse anti-infection assays were performed to investigate the in vivo effect of paeoniflorin combined with norfloxacin.Results: FIC results showed that paeoniflorin and norfloxacin exert a synergistic bactericidal effect. Evidence was brought that paeoniflorin reduces the S. suis AI-2 activity and significantly down-regulates the transcription of the FQ efflux pump gene. In addition, paeoniflorin can inhibit biofilm formation, thereby promoting the ability of norfloxacin to kill S. suis. Finally, we showed in a mouse model that paeoniflorin in association with norfloxacin is effective to treat S. suis infections.Conclusions: This study highlighted the inhibitory potential of paeoniflorin on the LuxS/AI-2 QS system of S. suis, and provided evidence that it can inhibit the FQ efflux pump and prevent biofilm formation to cooperate with norfloxacin in the treatment of resistant S. suis-related infections. [ABSTRACT FROM AUTHOR]