Dataset Information

Dual inhibitors of Pseudomonas aeruginosa virulence factors LecA and LasB.

ABSTRACT: Dual inhibitors of two key virulence factors of Pseudomonas aeruginosa, the lectin LecA and the protease LasB, open up an opportunity in the current antimicrobial-resistance crisis. A molecular hybridization approach enabled the discovery of potent, selective, and non-toxic thiol-based inhibitors, which simultaneously inhibit these two major extracellular virulence factors and therefore synergistically interfere with virulence. We further demonstrated that the dimerization of these monovalent dual inhibitors under physiological conditions affords divalent inhibitors of LecA with a 200-fold increase in binding affinity. The bifunctional LecA/LasB-blocker 12 showed superiority for the inhibition of virulence mediated by both targets over the individual inhibitors or combinations thereof in vitro. Our study sets the stage for a systematic exploration of dual inhibitors as pathoblockers for a more effective treatment of P. aeruginosa infections and the concept can certainly be extended to other targets and pathogens.

SUBMITTER: Metelkina O

PROVIDER: S-EPMC11339798 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dual inhibitors of <i>Pseudomonas aeruginosa</i> virulence factors LecA and LasB.

Metelkina Olga O Konstantinović Jelena J Klein Andreas A Shafiei Roya R Fares Mario M Alhayek Alaa A Yahiaoui Samir S Elgaher Walid A M WAM Haupenthal Jörg J Titz Alexander A Hirsch Anna K H AKH

Chemical science 20240722 33

Dual inhibitors of two key virulence factors of <i>Pseudomonas aeruginosa</i>, the lectin LecA and the protease LasB, open up an opportunity in the current antimicrobial-resistance crisis. A molecular hybridization approach enabled the discovery of potent, selective, and non-toxic thiol-based inhibitors, which simultaneously inhibit these two major extracellular virulence factors and therefore synergistically interfere with virulence. We further demonstrated that the dimerization of these monova ...[more]

PMID: 39183927

Similar Datasets

Project description: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.

Dataset Information

Dual inhibitors of Pseudomonas aeruginosa virulence factors LecA and LasB.

Publications

Dual inhibitors of <i>Pseudomonas aeruginosa</i> virulence factors LecA and LasB.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets