TY  - JOUR
A1  - Umstätter, Florian
A1  - Werner, Julia
A1  - Zerlin, Leah
A1  - Mühlberg, Eric
A1  - Kleist, Christian
A1  - Klika, Karel D.
A1  - Hertlein, Tobias
A1  - Beijer, Barbro
A1  - Domhan, Cornelius
A1  - Zimmermann, Stefan
A1  - Ohlsen, Knut
A1  - Haberkorn, Uwe
A1  - Mier, Walter
A1  - Uhl, Philipp
T1  - Impact of linker modification and PEGylation of vancomycin conjugates on structure-activity relationships and pharmacokinetics
JF  - Pharmaceuticals
N2  - As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics. The glycopeptide vancomycin is considered an antibiotic of last resort. Its use is challenged by bacterial strains exhibiting various types of resistance. Therefore, in this study, highly active polycationic peptide-vancomycin conjugates with varying linker characteristics or the addition of PEG moieties were synthesized to optimize pharmacokinetics while retaining or even increasing antimicrobial activity in comparison to vancomycin. The antimicrobial activity of the novel conjugates was determined by microdilution assays on susceptible and vancomycin-resistant bacterial strains. VAN1 and VAN2, the most promising linker-modified derivatives, were further characterized in vivo with molecular imaging and biodistribution studies in rodents, showing that the linker moiety influences both antimicrobial activity and pharmacokinetics. Encouragingly, VAN2 was able to undercut the resistance breakpoint in microdilution assays on vanB and vanC vancomycin-resistant enterococci. Out of all PEGylated derivatives, VAN:PEG1 and VAN:PEG3 were able to overcome vanC resistance. Biodistribution studies of the novel derivatives revealed significant changes in pharmacokinetics when compared with vancomycin. In conclusion, linker modification of vancomycin-polycationic peptide conjugates represents a promising strategy for the modulation of pharmacokinetic behavior while providing potent antimicrobial activity.
KW  - glycopeptide antibiotics
KW  - antimicrobial resistance
KW  - vancomycin
KW  - polycationic peptides
KW  - linker influence
KW  - pharmacokinetics
KW  - PEGylation
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255197
SN  - 1424-8247
VL  - 15
IS  - 2
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  -