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  - Masota, Nelson E.
A1  - Ohlsen, Knut
A1  - Schollmayer, Curd
A1  - Meinel, Lorenz
A1  - Holzgrabe, Ulrike
T1  - Isolation and characterization of galloylglucoses effective against multidrug-resistant strains of Escherichia coli and Klebsiella pneumoniae
JF  - Molecules
N2  - The search for new antibiotics against multidrug-resistant (MDR), Gram-negative bacteria is crucial with respect to filling the antibiotics development pipeline, which is subject to a critical shortage of novel molecules. Screening of natural products is a promising approach for identifying antimicrobial compounds hosting a higher degree of novelty. Here, we report the isolation and characterization of four galloylglucoses active against different MDR strains of Escherichia coli and Klebsiella pneumoniae. A crude acetone extract was prepared from Paeonia officinalis Linnaeus leaves, and bioautography-guided isolation of active compounds from the extract was performed by liquid–liquid extraction, as well as open column, flash, and preparative chromatographic methods. Isolated active compounds were characterized and elucidated by a combination of spectroscopic and spectrometric techniques. In vitro antimicrobial susceptibility testing was carried out on E. coli and K. pneumoniae using 2 reference strains and 13 strains hosting a wide range of MDR phenotypes. Furthermore, in vivo antibacterial activities were assessed using Galleria mellonella larvae, and compounds 1,2,3,4,6-penta-O-galloyl-β-d-glucose, 3-O-digalloyl-1,2,4,6-tetra-O-galloyl-β-d-glucose, 6-O-digalloyl-1,2,3,4-tetra-O-galloyl-β-d-glucose, and 3,6-bis-O-digalloyl-1,2,4-tri-O-galloyl-β-d-glucose were isolated and characterized. They showed minimum inhibitory concentration (MIC) values in the range of 2–256 µg/mL across tested bacterial strains. These findings have added to the number of known galloylglucoses from P. officinalis and highlight their potential against MDR Gram-negative bacteria.
KW  - antimicrobial resistance
KW  - Enterobacteriaceae
KW  - Paeonia
KW  - gallotannins
KW  - isolation
KW  - structural elucidation
KW  - Escherichia coli
KW  - Klebsiella pneumoniae
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286179
SN  - 1420-3049
VL  - 27
IS  - 15
ER  -