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13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine

We previously showed that berberine attenuates MexXY efflux-dependent aminoglycoside resistance in Pseudomonas aeruginosa. Here, we aimed to synthesize berberine derivatives with higher MexXY inhibitory activities. We synthesized 11 berberine derivatives, of which 13-(2-methylbenzyl) berberine (13-o...

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Autores principales: Kotani, Kenta, Matsumura, Mio, Morita, Yuji, Tomida, Junko, Kutsuna, Ryo, Nishino, Kunihiko, Yasuike, Shuji, Kawamura, Yoshiaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963850/
https://www.ncbi.nlm.nih.gov/pubmed/31698691
http://dx.doi.org/10.3390/antibiotics8040212
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author Kotani, Kenta
Matsumura, Mio
Morita, Yuji
Tomida, Junko
Kutsuna, Ryo
Nishino, Kunihiko
Yasuike, Shuji
Kawamura, Yoshiaki
author_facet Kotani, Kenta
Matsumura, Mio
Morita, Yuji
Tomida, Junko
Kutsuna, Ryo
Nishino, Kunihiko
Yasuike, Shuji
Kawamura, Yoshiaki
author_sort Kotani, Kenta
collection PubMed
description We previously showed that berberine attenuates MexXY efflux-dependent aminoglycoside resistance in Pseudomonas aeruginosa. Here, we aimed to synthesize berberine derivatives with higher MexXY inhibitory activities. We synthesized 11 berberine derivatives, of which 13-(2-methylbenzyl) berberine (13-o-MBB) but not its regiomers showed the most promising MexXY inhibitory activity. 13-o-MBB reduced the minimum inhibitory concentrations (MICs) of various aminoglycosides 4- to 128 fold for a highly multidrug resistant P. aeruginosa strain. Moreover, 13-o-MBB significantly reduced the MICs of gentamicin and amikacin in Achromobacter xylosoxidans and Burkholderia cepacia. The fractional inhibitory concentration indices indicated that 13-o-MBB acted synergistically with aminoglycosides in only MexXY-positive P. aeruginosa strains. Time-kill curves showed that 13-o-MBB or higher concentrations of berberine increased the bactericidal activity of gentamicin by inhibiting MexXY in P. aeruginosa. Our findings indicate that 13-o-MBB inhibits MexXY-dependent aminoglycoside drug resistance more strongly than berberine and that 13-o-MBB is a useful inhibitor of aminoglycoside drug resistance due to MexXY.
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spelling pubmed-69638502020-01-27 13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine Kotani, Kenta Matsumura, Mio Morita, Yuji Tomida, Junko Kutsuna, Ryo Nishino, Kunihiko Yasuike, Shuji Kawamura, Yoshiaki Antibiotics (Basel) Article We previously showed that berberine attenuates MexXY efflux-dependent aminoglycoside resistance in Pseudomonas aeruginosa. Here, we aimed to synthesize berberine derivatives with higher MexXY inhibitory activities. We synthesized 11 berberine derivatives, of which 13-(2-methylbenzyl) berberine (13-o-MBB) but not its regiomers showed the most promising MexXY inhibitory activity. 13-o-MBB reduced the minimum inhibitory concentrations (MICs) of various aminoglycosides 4- to 128 fold for a highly multidrug resistant P. aeruginosa strain. Moreover, 13-o-MBB significantly reduced the MICs of gentamicin and amikacin in Achromobacter xylosoxidans and Burkholderia cepacia. The fractional inhibitory concentration indices indicated that 13-o-MBB acted synergistically with aminoglycosides in only MexXY-positive P. aeruginosa strains. Time-kill curves showed that 13-o-MBB or higher concentrations of berberine increased the bactericidal activity of gentamicin by inhibiting MexXY in P. aeruginosa. Our findings indicate that 13-o-MBB inhibits MexXY-dependent aminoglycoside drug resistance more strongly than berberine and that 13-o-MBB is a useful inhibitor of aminoglycoside drug resistance due to MexXY. MDPI 2019-11-06 /pmc/articles/PMC6963850/ /pubmed/31698691 http://dx.doi.org/10.3390/antibiotics8040212 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kotani, Kenta
Matsumura, Mio
Morita, Yuji
Tomida, Junko
Kutsuna, Ryo
Nishino, Kunihiko
Yasuike, Shuji
Kawamura, Yoshiaki
13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine
title 13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine
title_full 13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine
title_fullStr 13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine
title_full_unstemmed 13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine
title_short 13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine
title_sort 13-(2-methylbenzyl) berberine is a more potent inhibitor of mexxy-dependent aminoglycoside resistance than berberine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963850/
https://www.ncbi.nlm.nih.gov/pubmed/31698691
http://dx.doi.org/10.3390/antibiotics8040212
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