Isoliquiritigenin targets las, rhl, and Pqs quorum sensing systems to mitigate the virulence and infection of Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic pathogen with high antibiotic resistance, often causing hard-to-treat infections. Its quorum sensing (QS) system regulates virulence and drug resistance. Targeting quorum sensing via QS inhibitors is a promising strategy to combat such infections. In this study, isoliquiritigenin, a natural chalcone compound, could inhibit QS-related gene expression (lasR, lasI, rhlR, rhlI, pqsA, pqsR, lasA, rhlA, phzA1) and reduced virulence factor production of Pseudomonas aeruginosa PAO1, including protease, elastase, pyocyanin, rhamnolipid, biofilm formation and motility at subinhibitory concentrations of 50 and 100 µg/mL. The pathogenicity of PAO1 could be also attenuated by isoliquiritigenin at the tested concentrations evidenced by in vitro and vivo infection analysis via Chinese cabbage, Drosophila melanogaster, and Caenorhabditis elegans modles. Isoliquiritigenin might exhibit QSI property by targeting the las, rhl, and pqs systems based on the molecular docking analysis and the infection analysis in mutants. As a novel QSI, isoliquiritigenin develop less tendency drug resistance to PAO1, at least during the 20 generations tested. Moreover, isoliquiritigenin could increase the sensitivity of P. aeruginosa to aminoglycosides of kanamycin, amikacin or tobramycin, enhancing P. aeruginosa infection treatment. Therefore, isoliquiritigenin could function as a potential QSI against P. aeruginosa infection, either separately or synergistically combined with aminoglycosides antibiotics.