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Article

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

1
Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy
2
Department of Materials, Environmental Sciences and Urban Planning, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy
3
Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Brullo Chiara
Molecules 2021, 26(21), 6644; https://doi.org/10.3390/molecules26216644
Received: 7 October 2021 / Revised: 28 October 2021 / Accepted: 29 October 2021 / Published: 2 November 2021
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. View Full-Text
Keywords: efflux pump inhibitors; Pseudomonas aeruginosa; berberine derivatives; molecular modeling; multidrug resistance efflux pump inhibitors; Pseudomonas aeruginosa; berberine derivatives; molecular modeling; multidrug resistance
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MDPI and ACS Style

Giorgini, G.; Mangiaterra, G.; Cedraro, N.; Laudadio, E.; Sabbatini, G.; Cantarini, M.; Minnelli, C.; Mobbili, G.; Frangipani, E.; Biavasco, F.; Galeazzi, R. Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights. Molecules 2021, 26, 6644. https://doi.org/10.3390/molecules26216644

AMA Style

Giorgini G, Mangiaterra G, Cedraro N, Laudadio E, Sabbatini G, Cantarini M, Minnelli C, Mobbili G, Frangipani E, Biavasco F, Galeazzi R. Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights. Molecules. 2021; 26(21):6644. https://doi.org/10.3390/molecules26216644

Chicago/Turabian Style

Giorgini, Giorgia, Gianmarco Mangiaterra, Nicholas Cedraro, Emiliano Laudadio, Giulia Sabbatini, Mattia Cantarini, Cristina Minnelli, Giovanna Mobbili, Emanuela Frangipani, Francesca Biavasco, and Roberta Galeazzi. 2021. "Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights" Molecules 26, no. 21: 6644. https://doi.org/10.3390/molecules26216644

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