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A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531014/ https://www.ncbi.nlm.nih.gov/pubmed/36204236 http://dx.doi.org/10.3389/fphar.2022.996871 |
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author | Bernabè, Giulia Marzaro, Giovanni Di Pietra, Giuseppe Otero, Ana Bellato, Massimo Pauletto, Anthony Scarpa, Melania Sut, Stefania Chilin, Adriana Dall’Acqua, Stefano Brun, Paola Castagliuolo, Ignazio |
author_facet | Bernabè, Giulia Marzaro, Giovanni Di Pietra, Giuseppe Otero, Ana Bellato, Massimo Pauletto, Anthony Scarpa, Melania Sut, Stefania Chilin, Adriana Dall’Acqua, Stefano Brun, Paola Castagliuolo, Ignazio |
author_sort | Bernabè, Giulia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9531014 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95310142022-10-05 A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa Bernabè, Giulia Marzaro, Giovanni Di Pietra, Giuseppe Otero, Ana Bellato, Massimo Pauletto, Anthony Scarpa, Melania Sut, Stefania Chilin, Adriana Dall’Acqua, Stefano Brun, Paola Castagliuolo, Ignazio Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2022-09-20 /pmc/articles/PMC9531014/ /pubmed/36204236 http://dx.doi.org/10.3389/fphar.2022.996871 Text en Copyright © 2022 Bernabè, Marzaro, Di Pietra, Otero, Bellato, Pauletto, Scarpa, Sut, Chilin, Dall’Acqua, Brun and Castagliuolo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Bernabè, Giulia Marzaro, Giovanni Di Pietra, Giuseppe Otero, Ana Bellato, Massimo Pauletto, Anthony Scarpa, Melania Sut, Stefania Chilin, Adriana Dall’Acqua, Stefano Brun, Paola Castagliuolo, Ignazio A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa |
title | A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa
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title_full | A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa
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title_fullStr | A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa
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title_full_unstemmed | A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa
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title_short | A novel phenolic derivative inhibits AHL-dependent quorum sensing signaling in Pseudomonas aeruginosa
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title_sort | novel phenolic derivative inhibits ahl-dependent quorum sensing signaling in pseudomonas aeruginosa |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531014/ https://www.ncbi.nlm.nih.gov/pubmed/36204236 http://dx.doi.org/10.3389/fphar.2022.996871 |
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