Berberine Derivatives as <i>Pseudomonas aeruginosa</i> MexXY-OprM Inhibitors: Activity and In Silico Insights
The natural alkaloid berberine has been demonstrated to inhibit the <i>Pseudomonas aeruginosa</i> 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 co...
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2021
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oai:doaj.org-article:0260bdc7601d46bcb7d1ad71a4ced2cb2021-11-11T18:36:43ZBerberine Derivatives as <i>Pseudomonas aeruginosa</i> MexXY-OprM Inhibitors: Activity and In Silico Insights10.3390/molecules262166441420-3049https://doaj.org/article/0260bdc7601d46bcb7d1ad71a4ced2cb2021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6644https://doaj.org/toc/1420-3049The natural alkaloid berberine has been demonstrated to inhibit the <i>Pseudomonas aeruginosa</i> 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 <i>P. aeruginosa</i> (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 Δ<i>mexXY</i> 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.Giorgia GiorginiGianmarco MangiaterraNicholas CedraroEmiliano LaudadioGiulia SabbatiniMattia CantariniCristina MinnelliGiovanna MobbiliEmanuela FrangipaniFrancesca BiavascoRoberta GaleazziMDPI AGarticleefflux pump inhibitors<i>Pseudomonas aeruginosa</i>berberine derivativesmolecular modelingmultidrug resistanceOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6644, p 6644 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
efflux pump inhibitors <i>Pseudomonas aeruginosa</i> berberine derivatives molecular modeling multidrug resistance Organic chemistry QD241-441 |
| spellingShingle |
efflux pump inhibitors <i>Pseudomonas aeruginosa</i> berberine derivatives molecular modeling multidrug resistance Organic chemistry QD241-441 Giorgia Giorgini Gianmarco Mangiaterra Nicholas Cedraro Emiliano Laudadio Giulia Sabbatini Mattia Cantarini Cristina Minnelli Giovanna Mobbili Emanuela Frangipani Francesca Biavasco Roberta Galeazzi Berberine Derivatives as <i>Pseudomonas aeruginosa</i> MexXY-OprM Inhibitors: Activity and In Silico Insights |
| description |
The natural alkaloid berberine has been demonstrated to inhibit the <i>Pseudomonas aeruginosa</i> 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 <i>P. aeruginosa</i> (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 Δ<i>mexXY</i> 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 |
article |
| author |
Giorgia Giorgini Gianmarco Mangiaterra Nicholas Cedraro Emiliano Laudadio Giulia Sabbatini Mattia Cantarini Cristina Minnelli Giovanna Mobbili Emanuela Frangipani Francesca Biavasco Roberta Galeazzi |
| author_facet |
Giorgia Giorgini Gianmarco Mangiaterra Nicholas Cedraro Emiliano Laudadio Giulia Sabbatini Mattia Cantarini Cristina Minnelli Giovanna Mobbili Emanuela Frangipani Francesca Biavasco Roberta Galeazzi |
| author_sort |
Giorgia Giorgini |
| title |
Berberine Derivatives as <i>Pseudomonas aeruginosa</i> MexXY-OprM Inhibitors: Activity and In Silico Insights |
| title_short |
Berberine Derivatives as <i>Pseudomonas aeruginosa</i> MexXY-OprM Inhibitors: Activity and In Silico Insights |
| title_full |
Berberine Derivatives as <i>Pseudomonas aeruginosa</i> MexXY-OprM Inhibitors: Activity and In Silico Insights |
| title_fullStr |
Berberine Derivatives as <i>Pseudomonas aeruginosa</i> MexXY-OprM Inhibitors: Activity and In Silico Insights |
| title_full_unstemmed |
Berberine Derivatives as <i>Pseudomonas aeruginosa</i> MexXY-OprM Inhibitors: Activity and In Silico Insights |
| title_sort |
berberine derivatives as <i>pseudomonas aeruginosa</i> mexxy-oprm inhibitors: activity and in silico insights |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/0260bdc7601d46bcb7d1ad71a4ced2cb |
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