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Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights

The natural alkaloid berberine has been demonstrated to inhibit the Pseudomonas aeruginosa multidrug efflux system MexXY-OprM, which is responsible for tobramycin extrusion by binding the inner membrane transporter MexY. To find a structure with improved inhibitory activity, we compared by molecular...

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Autores principales: Giorgini, Giorgia, Mangiaterra, Gianmarco, Cedraro, Nicholas, Laudadio, Emiliano, Sabbatini, Giulia, Cantarini, Mattia, Minnelli, Cristina, Mobbili, Giovanna, Frangipani, Emanuela, Biavasco, Francesca, Galeazzi, Roberta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587913/
https://www.ncbi.nlm.nih.gov/pubmed/34771051
http://dx.doi.org/10.3390/molecules26216644
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author Giorgini, Giorgia
Mangiaterra, Gianmarco
Cedraro, Nicholas
Laudadio, Emiliano
Sabbatini, Giulia
Cantarini, Mattia
Minnelli, Cristina
Mobbili, Giovanna
Frangipani, Emanuela
Biavasco, Francesca
Galeazzi, Roberta
author_facet Giorgini, Giorgia
Mangiaterra, Gianmarco
Cedraro, Nicholas
Laudadio, Emiliano
Sabbatini, Giulia
Cantarini, Mattia
Minnelli, Cristina
Mobbili, Giovanna
Frangipani, Emanuela
Biavasco, Francesca
Galeazzi, Roberta
author_sort Giorgini, Giorgia
collection PubMed
description The natural alkaloid berberine has been demonstrated to inhibit the Pseudomonas aeruginosa multidrug efflux system MexXY-OprM, which is responsible for tobramycin extrusion by binding the inner membrane transporter MexY. To find a structure with improved inhibitory activity, we compared by molecular dynamics investigations the binding affinity of berberine and three aromatic substituents towards the three polymorphic sequences of MexY found in P. aeruginosa (PAO1, PA7, and PA14). The synergy of the combinations of berberine or berberine derivatives/tobramycin against the same strains was then evaluated by checkerboard and time-kill assays. The in silico analysis evidenced different binding modes depending on both the structure of the berberine derivative and the specific MexY polymorphism. In vitro assays showed an evident MIC reduction (32-fold and 16-fold, respectively) and a 2–3 log greater killing effect after 2 h of exposure to the combinations of 13-(2-methylbenzyl)- and 13-(4-methylbenzyl)-berberine with tobramycin against the tobramycin-resistant strain PA7, a milder synergy (a 4-fold MIC reduction) against PAO1 and PA14, and no synergy against the ΔmexXY strain K1525, confirming the MexY-specific binding and the computational results. These berberine derivatives could thus be considered new hit compounds to select more effective berberine substitutions and their common path of interaction with MexY as the starting point for the rational design of novel MexXY-OprM inhibitors.
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spelling pubmed-85879132021-11-13 Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights Giorgini, Giorgia Mangiaterra, Gianmarco Cedraro, Nicholas Laudadio, Emiliano Sabbatini, Giulia Cantarini, Mattia Minnelli, Cristina Mobbili, Giovanna Frangipani, Emanuela Biavasco, Francesca Galeazzi, Roberta Molecules Article The natural alkaloid berberine has been demonstrated to inhibit the Pseudomonas aeruginosa multidrug efflux system MexXY-OprM, which is responsible for tobramycin extrusion by binding the inner membrane transporter MexY. To find a structure with improved inhibitory activity, we compared by molecular dynamics investigations the binding affinity of berberine and three aromatic substituents towards the three polymorphic sequences of MexY found in P. aeruginosa (PAO1, PA7, and PA14). The synergy of the combinations of berberine or berberine derivatives/tobramycin against the same strains was then evaluated by checkerboard and time-kill assays. The in silico analysis evidenced different binding modes depending on both the structure of the berberine derivative and the specific MexY polymorphism. In vitro assays showed an evident MIC reduction (32-fold and 16-fold, respectively) and a 2–3 log greater killing effect after 2 h of exposure to the combinations of 13-(2-methylbenzyl)- and 13-(4-methylbenzyl)-berberine with tobramycin against the tobramycin-resistant strain PA7, a milder synergy (a 4-fold MIC reduction) against PAO1 and PA14, and no synergy against the ΔmexXY strain K1525, confirming the MexY-specific binding and the computational results. These berberine derivatives could thus be considered new hit compounds to select more effective berberine substitutions and their common path of interaction with MexY as the starting point for the rational design of novel MexXY-OprM inhibitors. MDPI 2021-11-02 /pmc/articles/PMC8587913/ /pubmed/34771051 http://dx.doi.org/10.3390/molecules26216644 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Giorgini, Giorgia
Mangiaterra, Gianmarco
Cedraro, Nicholas
Laudadio, Emiliano
Sabbatini, Giulia
Cantarini, Mattia
Minnelli, Cristina
Mobbili, Giovanna
Frangipani, Emanuela
Biavasco, Francesca
Galeazzi, Roberta
Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
title Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
title_full Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
title_fullStr Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
title_full_unstemmed Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
title_short Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
title_sort berberine derivatives as pseudomonas aeruginosa mexxy-oprm inhibitors: activity and in silico insights
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587913/
https://www.ncbi.nlm.nih.gov/pubmed/34771051
http://dx.doi.org/10.3390/molecules26216644
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