Falcarindiol Isolated from Notopterygium incisum Inhibits the Quorum Sensing of Pseudomonas aeruginosa

Abstract

Quorum sensing (QS) is employed by the opportunistic pathogen <i>Pseudomonas aeruginosa</i> to regulate physiological behaviors and virulence. QS inhibitors (QSIs) are potential anti-virulence agents for the therapy of <i>P. aeruginosa</i> infection. During the screening for QSIs from Chinese herbal medicines, falcarindiol (the major constituent of <i>Notopterygium incisum</i>) exhibited QS inhibitory activity. The subinhibitory concentration of falcarindiol exerted significant inhibitory effects on the formation of biofilm and the production of virulence factors such as elastase, pyocyanin, and rhamnolipid. The mRNA expression of QS-related genes (<i>lasB</i>, <i>phzH</i>, <i>rhlA</i>, <i>lasI</i>, <i>rhlI</i>, <i>pqsA</i>, and <i>rhlR</i>) was downregulated by falcarindiol while that of <i>lasR</i> was not affected by falcarindiol. The transcriptional activation of the <i>lasI</i> promoter was inhibited by falcarindiol in the <i>P. aeruginosa</i> QSIS-<i>lasI</i> selector. Further experiments confirmed that falcarindiol inhibited the <i>las</i> system using the reporter strain <i>Escherichia coli</i> MG4/pKDT17. Electrophoretic mobility shift assay (EMSA) showed that falcarindiol inhibited the binding of the transcription factor LasR and the <i>lasI</i> promoter region. Molecular docking showed that falcarindiol interacted with the Tyr47 residue, leading to LasR instability. The decrease of LasR-mediated transcriptional activation was responsible for the reduction of downstream gene expression, which further inhibited virulence production. The inhibition mechanism of falcarindiol to LasR provides a theoretical basis for its medicinal application.