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Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides
Please always quote using this URN: urn:nbn:de:bvb:20-opus-215550
- 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‐foldMultidrug‐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.…
Author: | Florian Umstätter, Cornelius Domhan, Tobias Hertlein, Knut Ohlsen, Eric Mühlberg, Christian Kleist, Stefan Zimmermann, Barbro Beijer, Karel D. Klika, Uwe Haberkorn, Walter Mier, Philipp Uhl |
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URN: | urn:nbn:de:bvb:20-opus-215550 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Institut für Molekulare Infektionsbiologie |
Language: | English |
Parent Title (English): | Angewandte Chemie International Edition |
Year of Completion: | 2020 |
Volume: | 59 |
Issue: | 23 |
First Page: | 8823 |
Last Page: | 8827 |
Source: | Angewandte Chemie International Edition 2020, 59(23):8823–8827. DOI: 10.1002/anie.202002727 |
DOI: | https://doi.org/10.1002/anie.202002727 |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Tag: | antibiotics; bacterial resistance; glycopeptide antibiotics; peptide conjugates; vancomycin |
Release Date: | 2021/06/30 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |