Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
| Autor: | Nicholas Cedraro, Giulia Sabbatini, Mattia Cantarini, Roberta Galeazzi, Emiliano Laudadio, Francesca Biavasco, Emanuela Frangipani, Gianmarco Mangiaterra, Giorgia Giorgini, Cristina Minnelli, Giovanna Mobbili |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Berberine
In silico Pharmaceutical Science Chemistry Techniques Synthetic Microbial Sensitivity Tests Molecular Dynamics Simulation medicine.disease_cause berberine derivatives Article Analytical Chemistry Pseudomonas aeruginosa efflux pump inhibitors molecular modeling multidrug resistance Amino Acid Sequence Anti-Bacterial Agents Bacterial Proteins Binding Sites Drug Synergism Molecular Docking Simulation Molecular Structure Polymorphism Genetic Protein Binding Structure-Activity Relationship chemistry.chemical_compound QD241-441 Genetic Drug Discovery medicine Tobramycin Polymorphism Physical and Theoretical Chemistry Alkaloid Synthetic Organic Chemistry Rational design Chemistry Techniques Multiple drug resistance Biochemistry chemistry Chemistry (miscellaneous) Molecular Medicine Efflux medicine.drug |
| Zdroj: | Molecules Volume 26 Issue 21 Molecules, Vol 26, Iss 6644, p 6644 (2021) |
| ISSN: | 1420-3049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |