Attenuation of Pseudomonas aeruginosa Quorum Sensing by Natural Products: Virtual Screening, Evaluation and Biomolecular Interactions

Abstract

Natural products play vital roles against infectious diseases since ancient times and most drugs in use today are derived from natural sources. Worldwide, multi-drug resistance becomes a massive threat to the society with increasing mortality. Hence, it is very crucial to identify alternate strategies to control these ‘super bugs’. Pseudomonas aeruginosa is an opportunistic pathogen reported to be resistant to a large number of critically important antibiotics. Quorum sensing (QS) is a cell–cell communication mechanism, regulates the biofilm formation and virulence factors that endow pathogenesis in various bacteria including P. aeruginosa. In this study, we identified and evaluated quorum sensing inhibitors (QSIs) from plant-based natural products against P. aeruginosa. In silico studies revealed that catechin-7-xyloside (C7X), sappanol and butein were capable of interacting with LasR, a LuxR-type quorum sensing regulator of P. aeruginosa. In vitro assays suggested that these QSIs significantly reduced the biofilm formation, pyocyanin, elastase, and rhamnolipid without influencing the growth. Especially, butein reduced the biofilm formation up to 72.45% at 100 µM concentration while C7X and sappanol inhibited the biofilm up to 66% and 54.26% respectively. Microscale thermophoresis analysis revealed that C7X had potential interaction with LasR (KD = 933±369 nM) and thermal shift assay further confirmed the biomolecular interactions. These results suggested that QSIs are able to substantially obstruct the P. aeruginosa QS. Since LuxR-type transcriptional regulator homologues are present in numerous bacterial species, these QSIs may be developed as broad spectrum anti-infectives in the future.

Olive Leaf Extract Modulates Quorum Sensing Genes and Biofilm Formation in Multi-Drug Resistant Pseudomonas aeruginosa

“…Unlike conventional antibiotics which affect certain cellular metabolic process, the quorum sensing inhibitors (QSIs) are believed to hinder bacterial communication without imposing pressure on the bacteria, thus reducing the probability for the emerging of resistant strains existence [ 22 ]. As an example of plant-derived compounds, catechin-7-xyloside, sappanol, and butein were capable of interacting with LasR and significantly reduced the biofilm formation, pyocyanin, elastase, and rhamnolipid without influencing the growth of P. aeruginosa [ 23 ].…”

Paeonol Attenuates Quorum-Sensing Regulated Virulence and Biofilm Formation in Pseudomonas aeruginosa

“…Many bacteria sense and communicate with each other through quorum sensing, a gene regulatory mechanism that depends on cell density ( Waters and Bassler, 2005 ). Several naturally occurring compounds have been screened for their anti-QS and anti-biofilm activities in C. violaceum ( Paczkowski et al, 2017 ; Zhong et al, 2020 ). Some potential compounds with anti-QS activity were identified in the preliminary screening, including protocatechualdehyde, anisic aldehyde, carvacrol, and paeonol.…”

Identification of New Potential Inhibitors of Quorum Sensing through a Specialized Multi-Level Computational Approach

“…Over the years, the usage of computer-aided drug design (CADD) as a preliminary stage of drug design has increased, finding application in the study of many problems, including in the search for quorum-sensing inhibitors [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. This makes the entire process more cost-efficient and minimizes failures [ 37 ].…”