Novel ligustilide derivatives target quorum sensing system LasR/LasB and relieve inflammatory response against Pseudomonas aeruginosa infection

Abstract

The increasing antibiotic resistance driven by Pseudomonas aeruginosa typically leads to uncontrolled and persistent inflammatory damage, which is primarily attributed to the virulence and biofilms produced by the bacteria. Herein, we present a novel anti-infective drug strategy designed to inhibit the bacterial quorum sensing system, thereby attenuating P. aeruginosa virulence, and modulating inflammation from drug-resistant bacterial infections. We discovered new quorum sensing LasR/LasB inhibitors derived from the structural modification of a ligustilide derivative library. Of these compounds, 5f demonstrated significant inhibitory activity against LasB (LasB-gfp, IC50 = 8.7 μM) and a moderate inhibitory effect on P. aeruginosa biofilms (IC50 = 7.4 μM). Through live image analysis in a fluorescent protein–labeled zebrafish larva model, we observed that compound 5f significantly inhibited the migration of macrophages. Moreover, compound 5f effectively attenuated quorum sensing–mediated virulence factors and biofilm formation by P. aeruginosa. It also alleviated the inflammatory response by P. aeruginosa–infected macrophages through the downregulation of mitogen-activated protein kinase and NF-κB signal-transduction pathways. Notably, in vivo experiments, this compound demonstrated marked therapeutic effects in acute lung injury models induced by lipopolysaccharides from P. aeruginosa. These results indicate that compound 5f has the potential to be a novel anti-infective candidate against drug-resistant infections caused by P. aeruginosa.