Natural LuxS inhibitors enhance antibiotic sensitivity in multidrug-resistant Escherichia coli

The quorum sensing (QS) system facilitates bacterial cell-to-cell communication in response to population density, regulating various physiological processes such as biofilm formation and virulence gene expression. Inhibiting QS has emerged as a promising strategy to enhance the efficacy of conventional antibiotics against antibiotic-resistant bacterial pathogens. This study aimed to identify natural products that can specifically target LuxS, a key regulatory protein in the QS system of Escherichia coli (E. coli), through computational predictions of protein-natural product interactions. Among the 918 screened natural compounds, rhein (RHE), myricetin (MYR), and dihydromyricetin (DMY) exhibited the highest potential for binding to LuxS. Experimental validated confirmed the QS-inhibitory activity of these compounds, demonstrating that all three compounds significantly reduced autoinducer-2 (AI-2) synthesis, inhibited biofilm formation, and downregulated the expression of luxS and its associated genes. Furthermore, site-directed mutagenesis studies verified that MYR and DMY interact with specific binding sites on LuxS protein to modulate its activity. Notably, synergistic antibacterial effects were observed between RHE or DMY and colistin, as well as between DMY and chloramphenicol, against multidrug-resistant E. coli. In summary, this study identifies RHE, MYR, and DMY as promising QS inhibitors and supports the therapeutic potential of targeting the QS system to combat antibiotic-resistant bacterial infections.