Journal Article

A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa

Pauletto, Anthony, Di Pietra, Giuseppe, Dall’Acqua, Stefano, Brun, Paola, Marzaro, Giovanni, Castagliuolo, Ignazio, Chilin, Adriana, Bernabè, Giulia, Otero, Ana, Scarpa, Melania, Bellato, Massimo, Sut, Stefania

2022

Overview

Increasing antibiotic resistance and the decline in the pharmaceutical industry’s investments have amplified the need for novel treatments for multidrug-resistant bacteria. Quorum sensing (QS) inhibitors reduce pathogens’ virulence without selective pressure on bacteria and provide an alternative to conventional antibiotic-based therapies. P. aeruginosa uses complex QS signaling to control virulence and biofilm formation. We aimed to identify inhibitors of P. aeruginosa QS acting on acyl-homoserine lactones (AHL)-mediated circuits. Bioluminescence and qRT-PCR assays were employed to screen a library of 81 small phenolic derivatives to reduce AHL-dependent signaling. We identified GM-50 as the most active compound inhibiting the expression of AHL-regulated genes but devoid of cytotoxic activity in human epithelial cells and biocidal effects on bacteria. GM-50 reduces virulence factors such as rhamnolipids, pyocyanin, elastase secretion, and swarming motility in P. aeruginosa PAO1 laboratory strain. By molecular docking, we provide evidence that GM-50 highly interacts with RhlR. GM-50 significantly improved aztreonam-mediated biofilm disruption. Moreover, GM-50 prevents adhesion of PAO1 and inflammatory damage in the human A549 cell line and protects Galleria mellonella from PAO1-mediated killing. GM-50 significantly reduces virulence factors in 20 P. aeruginosa clinical isolates from patients with respiratory tract infections. In conclusion, GM-50 inhibits AHL-signaling, reduces virulence factors, enhances the anti-biofilm activity of aztreonam, and protects G. mellonella larvae from damage induced by P. aeruginosa . Since GM-50 is active on clinical strains, it represents a starting point for identifying and developing new phenolic derivatives acting as QS-inhibitors in P. aeruginosa infections.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Antibiotic resistance / Antibiotics / Aztreonam / Bacteria / Bacterial infections / biofilm / Biofilms / Bioluminescence / Chronic obstructive pulmonary disease / Circuits / Clinical isolates / Coronaviruses / COVID-19 / Cytotoxicity / Drug resistance / Elastase / Epithelial cells / Lactones / Libraries / Metabolism / molecular docking / Multidrug resistance / Pandemics / Pathogens / Pharmaceutical industry / Pharmacology / Phenolic compounds / Phenols / Pyocyanin / Quorum sensing / quorum sensing inhibitors / Respiratory tract infection / RhlR protein / Virulence / Virulence factors