TY  - JOUR
A1  - Mühlberg, Eric
A1  - Umstätter, Florian
A1  - Domhan, Cornelius
A1  - Hertlein, Tobias
A1  - Ohlsen, Knut
A1  - Krause, Andreas
A1  - Kleist, Christian
A1  - Beijer, Barbro
A1  - Zimmermann, Stefan
A1  - Haberkorn, Uwe
A1  - Mier, Walter
A1  - Uhl, Philipp
T1  - Vancomycin-lipopeptide conjugates with high antimicrobial activity on vancomycin-resistant enterococci
JF  - Pharmaceuticals
N2  - 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.
KW  - antibiotics
KW  - multidrug-resistant bacteria
KW  - enterococci
KW  - vancomycin
KW  - structural modification
KW  - fatty acids
KW  - polycationic peptides
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205879
SN  - 1424-8247
VL  - 13
IS  - 6
ER  - 
TY  - JOUR
A1  - Umstätter, Florian
A1  - Domhan, Cornelius
A1  - Hertlein, Tobias
A1  - Ohlsen, Knut
A1  - Mühlberg, Eric
A1  - Kleist, Christian
A1  - Zimmermann, Stefan
A1  - Beijer, Barbro
A1  - Klika, Karel D.
A1  - Haberkorn, Uwe
A1  - Mier, Walter
A1  - Uhl, Philipp
T1  - Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides
JF  - Angewandte Chemie International Edition
N2  - 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.
KW  - antibiotics
KW  - bacterial resistance
KW  - glycopeptide antibiotics
KW  - peptide conjugates
KW  - vancomycin
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215550
VL  - 59
IS  - 23
SP  - 8823
EP  - 8827
ER  -