Modifikation von Vancomycin zur Überwindung von Antibiotika-Resistenzen
Zusammenfassung der Projektergebnisse
In summary, vancomycin conjugation to polycationic peptides represents a promising tool and convincingly illustrates a new strategy for the development of highly potent and non-toxic antimicrobial substances by structural modification of already approved drugs to combat one of the biggest challenges in today's medicine-multidrug-resistant bacteria. Furthermore, peptide conjugation allows controlling the biodistribution and excretion profile of novel compounds making them more flexible for their broad application against a variety of multidrug-resistant bacteria. However, the current lead candidate FU002 (hexa-arginine modified vancomycin) shows, besides its high antimicrobial activity (proven in vitro and in vivo) two major drawbacks: low oral bioavailability (which can be neglected for treatment of nosocomial infections) but also short plasma half-life. In order to improve its pharmacokinetics, several conjugates varying the linker moiety and PEGylated ones were synthesized. In this part of the project, we demonstrated the significant influence of linker characteristics on both the antimicrobial potential and the pharmacokinetics of vancomycin conjugates. Although pharmacokinetic behavior could be modulated by changing the linker moiety of the conjugates, as well as by the PEGylation of the previously described FU002, even slight modifications could result in a significant decrease in antimicrobial activity. Nevertheless, the conjugates were able to enhance activity against vancomycin-resistant bacteria in comparison to vancomycin. Based on the absence of hemolytic activity, it was possible to design conjugates with encouraging properties. In one further part of this project, we combined recently published approaches of vancomycin modifications (polycationic peptides and fatty acids) in order to investigate the structure-activity relationship of the synthesized conjugates with respect to the antimicrobial activity on vancomycin-resistant enterococci. The data supports the use of lauric acid in lipopeptide conjugates and highlights the importance of the modification site. Therefore, other structural modifications could be investigated with varying derivatization strategies.
Projektbezogene Publikationen (Auswahl)
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Inside Back Cover: Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides (Angew. Chem. Int. Ed. 23/2020). Angewandte Chemie International Edition, 59(23), 9192-9192.
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
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Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides. Angewandte Chemie International Edition, 59(23), 8823-8827.
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
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Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci. Pharmaceuticals, 13(6), 110.
Mühlberg, Eric; Umstätter, Florian; Domhan, Cornelius; Hertlein, Tobias; Ohlsen, Knut; Krause, Andreas; Kleist, Christian; Beijer, Barbro; Zimmermann, Stefan; Haberkorn, Uwe; Mier, Walter & Uhl, Philipp
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Überwindung von Vancomycinresistenzen durch Modifikation mit polykationischen Peptiden. Angewandte Chemie, 132(23), 8908-8912.
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
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Peptide conjugation of glycopeptide antibiotics leads to conjugates that overcome all types of resistance. Transporter- und Barrieretage, Bad Herrenalb 2021. Talk
Florian Umstätter
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Polycationic peptide conjugates of vancomycin overcome all types of vancomycin resistance. Talk. International PhD Student & Postdoc Meeting of the German Pharmaceutical Society (DPhG), online
Florian Umstätter
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Impact of Linker Modification and PEGylation of Vancomycin Conjugates on Structure-Activity Relationships and Pharmacokinetics. Pharmaceuticals, 15(2), 159.
Umstätter, Florian; Werner, Julia; Zerlin, Leah; Mühlberg, Eric; Kleist, Christian; Klika, Karel D.; Hertlein, Tobias; Beijer, Barbro; Domhan, Cornelius; Zimmermann, Stefan; Ohlsen, Knut; Haberkorn, Uwe; Mier, Walter & Uhl, Philipp
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ROVANCE – A Platform Technology to Overcome Bacterial Resistance. Talk. 5th International CaparicaConference in Antibiotic Resistance 2022
Florian Umstätter
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Vancomycin-Lipopeptide Conjugates With High Antimicrobial Activity on Vancomycin-Reistant Enterococci. Poster. 5th International Caparica Conference in Antibiotic Resistance 2022
Eric Mühlberg
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ROVANCE – Resistance Overcoming Antibiotics New Chemical Entities: A Platform Technology to Overcome Bacterial Resistance. Talk. Tagung der Deutschen Pharmazeutischen Gesellschaft (DPhG), 2023, Tübingen
Philipp Uhl
