The AhR ligand phthiocol and vitamin K analogs as quorum sensing inhibitors.

The aryl hydrocarbon receptor (AhR) protein senses microbial-secreted metabolites to trigger the host's innate immune system. The quinolone signal (PQS) and (MTb) metabolite phthiocol (Pht) are both ligands of AhR with similar chemical structures. As PQS is an essential quorum-sensing molecule that regulates a wide range of virulence factors in , we hypothesized that Pht and its analogs are potential quorum-sensing inhibitors (QSIs) with immune-modulating functions. In this study, we demonstrated that Pht was able to inhibit the QS system and reduce both biofilm formation and the production of pyocyanin. Molecular docking analysis suggested that Pht competes with PQS at the binding site of its receptor, PqsR. An electrophoretic mobility shift assay confirmed the Pht-PqsR interaction and showed that Pht attenuated PqsR from binding to the promoter. Proteomic analysis showed that synthesis of the key QS proteins decreased upon the addition of Pht to the bacterial cultures. Furthermore, Pht analogs vitamins K (Phylloquinone), K (Menaquinones), and K (Menadione) were also showed to inhibit the QS system while able to activate the AhR signaling pathways. Our study suggests that the AhR ligands Pht and its vitamin K analogs are promising QSIs for the alternative treatment of infections.