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Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides
Multidrug‐resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323874/ https://www.ncbi.nlm.nih.gov/pubmed/32190958 http://dx.doi.org/10.1002/anie.202002727 |
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author | Umstätter, Florian Domhan, Cornelius Hertlein, Tobias Ohlsen, Knut Mühlberg, Eric Kleist, Christian Zimmermann, Stefan Beijer, Barbro Klika, Karel D. Haberkorn, Uwe Mier, Walter Uhl, Philipp |
author_facet | Umstätter, Florian Domhan, Cornelius Hertlein, Tobias Ohlsen, Knut Mühlberg, Eric Kleist, Christian Zimmermann, Stefan Beijer, Barbro Klika, Karel D. Haberkorn, Uwe Mier, Walter Uhl, Philipp |
author_sort | Umstätter, Florian |
collection | PubMed |
description | Multidrug‐resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site‐specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000‐fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d‐Ala‐d‐Ala revealed a mode of action beyond inhibition of cell‐wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics. |
format | Online Article Text |
id | pubmed-7323874 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73238742020-06-30 Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides Umstätter, Florian Domhan, Cornelius Hertlein, Tobias Ohlsen, Knut Mühlberg, Eric Kleist, Christian Zimmermann, Stefan Beijer, Barbro Klika, Karel D. Haberkorn, Uwe Mier, Walter Uhl, Philipp Angew Chem Int Ed Engl Communications Multidrug‐resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site‐specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000‐fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d‐Ala‐d‐Ala revealed a mode of action beyond inhibition of cell‐wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics. John Wiley and Sons Inc. 2020-04-21 2020-06-02 /pmc/articles/PMC7323874/ /pubmed/32190958 http://dx.doi.org/10.1002/anie.202002727 Text en © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Communications Umstätter, Florian Domhan, Cornelius Hertlein, Tobias Ohlsen, Knut Mühlberg, Eric Kleist, Christian Zimmermann, Stefan Beijer, Barbro Klika, Karel D. Haberkorn, Uwe Mier, Walter Uhl, Philipp Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides |
title | Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides |
title_full | Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides |
title_fullStr | Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides |
title_full_unstemmed | Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides |
title_short | Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides |
title_sort | vancomycin resistance is overcome by conjugation of polycationic peptides |
topic | Communications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323874/ https://www.ncbi.nlm.nih.gov/pubmed/32190958 http://dx.doi.org/10.1002/anie.202002727 |
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