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Open AccessArticle

Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci

1
Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
2
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany
3
Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Straße 2/D15, 97080 Würzburg, Germany
4
Department of Medical Microbiology and Hygiene, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg Germany
5
Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 260, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Pharmaceuticals 2020, 13(6), 110; https://doi.org/10.3390/ph13060110
Received: 23 April 2020 / Revised: 26 May 2020 / Accepted: 27 May 2020 / Published: 29 May 2020
(This article belongs to the Special Issue Glycopeptide Antibiotics 2020)
Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria. View Full-Text
Keywords: antibiotics; multidrug-resistant bacteria; enterococci; vancomycin; structural modification; fatty acids; polycationic peptides antibiotics; multidrug-resistant bacteria; enterococci; vancomycin; structural modification; fatty acids; polycationic peptides
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MDPI and ACS Style

Mühlberg, E.; Umstätter, F.; Domhan, C.; Hertlein, T.; Ohlsen, K.; Krause, A.; Kleist, C.; Beijer, B.; Zimmermann, S.; Haberkorn, U.; Mier, W.; Uhl, P. Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci. Pharmaceuticals 2020, 13, 110.

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