Journal Article

Quercetin: a promising virulence inhibitor of Pseudomonas aeruginosa LasB in vitro

Ren, Yanying, Liu, Ying, Liu, Xinwei, Li, Dengzhou, You, Xiaojuan, Yang, Ximing, Li, Yongwei, Fei, Bing, Zhu, Rui, Guo, Mengyu

2024

Overview

With the inappropriate use of antibiotics, antibiotic resistance has emerged as a major dilemma for patients infected with Pseudomonas aeruginosa . Elastase B (LasB), a crucial extracellular virulence factor secreted by P. aeruginosa , has been identified as a key target for antivirulence therapy. Quercetin, a natural flavonoid, exhibits promising potential as an antivirulence agent. We aim to evaluate the impact of quercetin on P. aeruginosa LasB and elucidate the underlying mechanism. Molecular docking and molecular dynamics simulation revealed a rather favorable intermolecular interaction between quercetin and LasB. At the sub-MICs of ≤256 μg/ml, quercetin was found to effectively inhibit the production and activity of LasB elastase, as well as downregulate the transcription level of the lasB gene in both PAO1 and clinical strains of P. aeruginosa . Through correlation analysis, significant positive correlations were shown between the virulence gene lasB and the QS system regulatory genes lasI , lasR , rhlI , and rhlR in clinical strains of P. aeruginosa . Then, we found the lasB gene expression and LasB activity were significantly deficient in PAO1 ΔlasI and ΔlasIΔrhlI mutants. In addition, quercetin significantly downregulated the expression levels of regulated genes lasI , lasR , rhlI, rhlR , pqsA , and pqsR as well as effectively attenuated the synthesis of signaling molecules 3-oxo-C12-HSL and C4-HSL in the QS system of PAO1. Quercetin was also able to compete with the natural ligands OdDHL, BHL, and PQS for binding to the receptor proteins LasR, RhlR, and PqsR, respectively, resulting in the formation of more stabilized complexes. Taken together, quercetin exhibits enormous potential in combating LasB production and activity by disrupting the QS system of P. aeruginosa in vitro , thereby offering an alternative approach for the antivirulence therapy of P. aeruginosa infections. Key points • Quercetin diminished the content and activity of LasB elastase of P. aeruginosa. • Quercetin inhibited the QS system activity of P. aeruginosa. • Quercetin acted on LasB based on the QS system.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: Anti-infective agents / Antibiotic resistance / Antibiotics / Applied Microbial and Cell Physiology / Biomedical and Life Sciences / Biotechnology / chemical interactions / Chemical synthesis / Control / Correlation analysis / Down-regulation / Elastase / Flavonoids / Gene expression / Genes / Health aspects / Humans / Life Sciences / ligands / Microbial Genetics and Genomics / Microbiology / Molecular docking / Molecular Docking Simulation / Molecular dynamics / Pancreatic Elastase / Pseudomonas aeruginosa / Pseudomonas aeruginosa - genetics / Quercetin / Quercetin - pharmacology / RhlR protein / Testing / therapeutics / Virulence / Virulence (Microbiology) / Virulence factors