Abstract
Bacteria have evolved multiple strategies for causing infections that include producing virulence factors, undertaking motility, developing biofilms, and invading host cells. N-acylhomoserine lactone (AHL)-mediated quorum sensing (QS) tightly regulates the expression of multiple virulence factors in the opportunistic pathogenic bacterium Pseudomonas aeruginosa. Thus, inhibiting QS could lead to health benefits. In this study, we demonstrate an anti-virulence activity of a cranberry extract rich in proanthocyanidins (cerPAC) against P. aeruginosa in the model host Drosophila melanogaster and show this is mediated by QS interference. cerPAC reduced the production of QS-regulated virulence determinants and protected D. melanogaster from fatal infection by P. aeruginosa PA14. Quantification of AHL production using liquid chromatography-mass spectrometry confirmed that cerPAC effectively reduced the level of AHLs produced by the bacteria. Furthermore, monitoring QS signaling gene expression revealed that AHL synthases LasI/RhlI and QS transcriptional regulators LasR/RhlR genes were inhibited and antagonized, respectively, by cerPAC. Molecular docking studies suggest that cranberry-derived proanthocyanidin binds to QS transcriptional regulators, mainly interacting with their ligand binding sites. These findings provide insights into the underlying mechanisms of action of a cerPAC to restrict the virulence of P. aeruginosa and can have implications in the development of alternative approaches to control infections.
Highlights
Host cell cytoskeleton in vitro[20]
Our results clearly show the anti-infectious properties of a cranberry extract rich in proanthocyanidins (cerPAC) against P. aeruginosa strain PA14 and reveal the multi-modal action of cerPAC in impairing quorum sensing (QS) function
The search for QS inhibitors or quenchers is a promising strategy aimed at development of innovative anti-microbial strategy to attenuate the virulence of infectious bacteria
Summary
Host cell cytoskeleton in vitro[20]. While many studies have suggested that consumption of cranberry-derived materials, namely cranberry capsules and cranberry juice, is effective in preventing bacterial infections[22,23,24,25,26], few have looked at the effects of these cranberry-derived materials in vitro and in vivo after consumption[24,27,28]. Not much attention has been given to the anti-virulence properties of cPACs. P. aeruginosa is an opportunistic and versatile γ-proteobacterium that readily develops antibiotic resistance and is responsible for various infections affecting immunocompromised individuals, such as those suffering from cystic fibrosis[29,30,31]. The Las system is positioned at the top of the QS hierarchy and uses N-3-(oxo-dodecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) as its signal molecule, and involves LasI and LasR as the synthase and regulator, respectively[35,36]. The Rhl system uses N-butanoyl-L-homoserine lactone (C4-HSL) as its signal, and involves RhlI and RhlR as the synthase and regulator, respectively[35,36]. The LasR initiates the QS regulatory systems, partially activates the transcription of RhlR and other regulators of Pseudomonas quinolone signal (PQS) and integrated quorum sensing (IQS) systems[33,37]. Our results clearly show the anti-infectious properties of a cerPAC against P. aeruginosa strain PA14 and reveal the multi-modal action of cerPAC in impairing QS function
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