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Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis
Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1–15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure–activity relationship (SAR) analysis were...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503621/ https://www.ncbi.nlm.nih.gov/pubmed/32825366 http://dx.doi.org/10.3390/molecules25173788 |
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author | Witek, Karolina Latacz, Gniewomir Kaczor, Aneta Czekajewska, Joanna Żesławska, Ewa Chudzik, Anna Karczewska, Elżbieta Nitek, Wojciech Kieć-Kononowicz, Katarzyna Handzlik, Jadwiga |
author_facet | Witek, Karolina Latacz, Gniewomir Kaczor, Aneta Czekajewska, Joanna Żesławska, Ewa Chudzik, Anna Karczewska, Elżbieta Nitek, Wojciech Kieć-Kononowicz, Katarzyna Handzlik, Jadwiga |
author_sort | Witek, Karolina |
collection | PubMed |
description | Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1–15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure–activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter. |
format | Online Article Text |
id | pubmed-7503621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75036212020-09-27 Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis Witek, Karolina Latacz, Gniewomir Kaczor, Aneta Czekajewska, Joanna Żesławska, Ewa Chudzik, Anna Karczewska, Elżbieta Nitek, Wojciech Kieć-Kononowicz, Katarzyna Handzlik, Jadwiga Molecules Article Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1–15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure–activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter. MDPI 2020-08-20 /pmc/articles/PMC7503621/ /pubmed/32825366 http://dx.doi.org/10.3390/molecules25173788 Text en © 2020 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 Witek, Karolina Latacz, Gniewomir Kaczor, Aneta Czekajewska, Joanna Żesławska, Ewa Chudzik, Anna Karczewska, Elżbieta Nitek, Wojciech Kieć-Kononowicz, Katarzyna Handzlik, Jadwiga Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis |
title | Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis |
title_full | Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis |
title_fullStr | Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis |
title_full_unstemmed | Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis |
title_short | Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis |
title_sort | phenylpiperazine 5,5-dimethylhydantoin derivatives as first synthetic inhibitors of msr(a) efflux pump in staphylococcus epidermidis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503621/ https://www.ncbi.nlm.nih.gov/pubmed/32825366 http://dx.doi.org/10.3390/molecules25173788 |
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