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Keywords = MexXY multidrug efflux system

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15 pages, 4781 KB  
Article
Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights
by Giorgia Giorgini, Gianmarco Mangiaterra, Nicholas Cedraro, Emiliano Laudadio, Giulia Sabbatini, Mattia Cantarini, Cristina Minnelli, Giovanna Mobbili, Emanuela Frangipani, Francesca Biavasco and Roberta Galeazzi
Molecules 2021, 26(21), 6644; https://doi.org/10.3390/molecules26216644 - 2 Nov 2021
Cited by 16 | Viewed by 3942
Abstract
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 [...] Read more.
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. Full article
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6 pages, 1065 KB  
Communication
Overexpression of the MexXY Multidrug Efflux System Correlates with Deficient Pyoverdine Production in Pseudomonas aeruginosa
by Kei Ikarashi, Ryo Kutsuna, Junko Tomida, Yoshiaki Kawamura and Yuji Morita
Antibiotics 2021, 10(6), 658; https://doi.org/10.3390/antibiotics10060658 - 31 May 2021
Cited by 5 | Viewed by 3822
Abstract
Multidrug-resistant Pseudomonas aeruginosa poses a serious problem due to hospital- and healthcare-associated infections. A major drug resistance mechanism of P. aeruginosa involves active efflux via resistance nodulation cell division (RND)-type multidrug efflux pumps of which MexXY is increasingly recognized as a primary determinant [...] Read more.
Multidrug-resistant Pseudomonas aeruginosa poses a serious problem due to hospital- and healthcare-associated infections. A major drug resistance mechanism of P. aeruginosa involves active efflux via resistance nodulation cell division (RND)-type multidrug efflux pumps of which MexXY is increasingly recognized as a primary determinant of aminoglycoside resistance in P. aeruginosa. MexXY overexpression is often observed in drug-resistant P. aeruginosa clinical isolates. MexXY deficiency increased pyoverdine production in all four P. aeruginosa strains we tested. MexXY-overproducing multidrug-resistant P. aeruginosa PA7 exhibited the greatest effect among the strains. Complementation with a MexXY-expressing plasmid restored low-level pyoverdine production in a MexXY-deficient P. aeruginosa mutant from PA7, indicating that MexXY expression decreases pyoverdine production. Because P. aeruginosa produces pyoverdine to acquire iron, MexXY-deficient mutants might be more susceptible to iron deficiency than MexXY-producing strains or might require extra iron. High-risk clones of multidrug-resistant P. aeruginosa reportedly tend to be MexXY overproducers but defective pyoverdine producers. This study suggests that P. aeruginosa reduces production of a virulence factor after acquiring a drug resistance factor. Full article
(This article belongs to the Special Issue Antimicrobial Resistance in Gram-Negative Bacteria, 2nd Edition)
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