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  -