Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE

The ability of the bacterial pathogen Pseudomonas aeruginosa to cause both chronic and acute infections mainly relies on its capacity to finely modulate the expression of virulence factors through a complex network of regulatory circuits, including the pqs quorum sensing (QS) system. While in most Q...

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Autores principales:	Valerio Baldelli, Francesca D’Angelo, Viola Pavoncello, Ersilia Vita Fiscarelli, Paolo Visca, Giordano Rampioni, Livia Leoni
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2020
Materias:	pseudomonas aeruginosa antivirulence strategy quorum sensing inhibition nitrofurazone erythromycin estolate screening pqse Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/7e2d2cbeaef94dbdacc17226a46ffa91
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spelling	oai:doaj.org-article:7e2d2cbeaef94dbdacc17226a46ffa912021-11-17T14:21:58ZIdentification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE2150-55942150-560810.1080/21505594.2020.1770508https://doaj.org/article/7e2d2cbeaef94dbdacc17226a46ffa912020-12-01T00:00:00Zhttp://dx.doi.org/10.1080/21505594.2020.1770508https://doaj.org/toc/2150-5594https://doaj.org/toc/2150-5608The ability of the bacterial pathogen Pseudomonas aeruginosa to cause both chronic and acute infections mainly relies on its capacity to finely modulate the expression of virulence factors through a complex network of regulatory circuits, including the pqs quorum sensing (QS) system. While in most QS systems the signal molecule/receptor complexes act as global regulators that modulate the expression of QS-controlled genes, the main effector protein of the pqs system is PqsE. This protein is involved in the synthesis of the QS signal molecules 2-alkyl-4(1H)-quinolones (AQs), but it also modulates the expression of genes involved in virulence factors production and biofilm formation via AQ-independent pathway(s). P. aeruginosa pqsE mutants disclose attenuated virulence in plant and animal infection models, hence PqsE is considered a good target for the development of antivirulence drugs against P. aeruginosa. In this study, the negative regulation exerted by PqsE on its own transcription has been exploited to develop a screening system for the identification of PqsE inhibitors in a library of FDA-approved drugs. This led to the identification of nitrofurazone and erythromycin estolate, two antibiotic compounds that reduce the expression of PqsE-dependent virulence traits and biofilm formation in the model strain P. aeruginosa PAO1 at concentrations far below those affecting the bacterial growth rate. Notably, both drugs reduce the production of the PqsE-controlled virulence factor pyocyanin also in P. aeruginosa strains isolated from cystic fibrosis patients, and do not antagonize the activity of antibiotics commonly used to treat P. aeruginosa infection.Valerio BaldelliFrancesca D’AngeloViola PavoncelloErsilia Vita FiscarelliPaolo ViscaGiordano RampioniLivia LeoniTaylor & Francis Grouparticlepseudomonas aeruginosaantivirulence strategyquorum sensing inhibitionnitrofurazoneerythromycin estolatescreeningpqseInfectious and parasitic diseasesRC109-216ENVirulence, Vol 11, Iss 1, Pp 652-668 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	pseudomonas aeruginosa antivirulence strategy quorum sensing inhibition nitrofurazone erythromycin estolate screening pqse Infectious and parasitic diseases RC109-216
spellingShingle	pseudomonas aeruginosa antivirulence strategy quorum sensing inhibition nitrofurazone erythromycin estolate screening pqse Infectious and parasitic diseases RC109-216 Valerio Baldelli Francesca D’Angelo Viola Pavoncello Ersilia Vita Fiscarelli Paolo Visca Giordano Rampioni Livia Leoni Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE
description	The ability of the bacterial pathogen Pseudomonas aeruginosa to cause both chronic and acute infections mainly relies on its capacity to finely modulate the expression of virulence factors through a complex network of regulatory circuits, including the pqs quorum sensing (QS) system. While in most QS systems the signal molecule/receptor complexes act as global regulators that modulate the expression of QS-controlled genes, the main effector protein of the pqs system is PqsE. This protein is involved in the synthesis of the QS signal molecules 2-alkyl-4(1H)-quinolones (AQs), but it also modulates the expression of genes involved in virulence factors production and biofilm formation via AQ-independent pathway(s). P. aeruginosa pqsE mutants disclose attenuated virulence in plant and animal infection models, hence PqsE is considered a good target for the development of antivirulence drugs against P. aeruginosa. In this study, the negative regulation exerted by PqsE on its own transcription has been exploited to develop a screening system for the identification of PqsE inhibitors in a library of FDA-approved drugs. This led to the identification of nitrofurazone and erythromycin estolate, two antibiotic compounds that reduce the expression of PqsE-dependent virulence traits and biofilm formation in the model strain P. aeruginosa PAO1 at concentrations far below those affecting the bacterial growth rate. Notably, both drugs reduce the production of the PqsE-controlled virulence factor pyocyanin also in P. aeruginosa strains isolated from cystic fibrosis patients, and do not antagonize the activity of antibiotics commonly used to treat P. aeruginosa infection.
format	article
author	Valerio Baldelli Francesca D’Angelo Viola Pavoncello Ersilia Vita Fiscarelli Paolo Visca Giordano Rampioni Livia Leoni
author_facet	Valerio Baldelli Francesca D’Angelo Viola Pavoncello Ersilia Vita Fiscarelli Paolo Visca Giordano Rampioni Livia Leoni
author_sort	Valerio Baldelli
title	Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE
title_short	Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE
title_full	Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE
title_fullStr	Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE
title_full_unstemmed	Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE
title_sort	identification of fda-approved antivirulence drugs targeting the pseudomonas aeruginosa quorum sensing effector protein pqse
publisher	Taylor & Francis Group
publishDate	2020
url	https://doaj.org/article/7e2d2cbeaef94dbdacc17226a46ffa91
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Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE

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