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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
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. |
format | Online Article Text |
id | pubmed-8587913 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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