@article{MuehlbergUmstaetterDomhanetal.2020,
  author    = {M{\"u}hlberg, Eric and Umst{\"a}tter, Florian and Domhan, Cornelius and Hertlein, Tobias and Ohlsen, Knut and Krause, Andreas and Kleist, Christian and Beijer, Barbro and Zimmermann, Stefan and Haberkorn, Uwe and Mier, Walter and Uhl, Philipp},
  title     = {Vancomycin-lipopeptide conjugates with high antimicrobial activity on vancomycin-resistant enterococci},
  series = {Pharmaceuticals},
  volume    = {13},
  journal   = {Pharmaceuticals},
  number    = {6},
  issn      = {1424-8247},
  doi       = {10.3390/ph13060110},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205879},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{UmstaetterWernerZerlinetal.2022,
  author    = {Umst{\"a}tter, Florian and Werner, Julia and Zerlin, Leah and M{\"u}hlberg, Eric and Kleist, Christian and Klika, Karel D. and Hertlein, Tobias and Beijer, Barbro and Domhan, Cornelius and Zimmermann, Stefan and Ohlsen, Knut and Haberkorn, Uwe and Mier, Walter and Uhl, Philipp},
  title     = {Impact of linker modification and PEGylation of vancomycin conjugates on structure-activity relationships and pharmacokinetics},
  series = {Pharmaceuticals},
  volume    = {15},
  journal   = {Pharmaceuticals},
  number    = {2},
  issn      = {1424-8247},
  doi       = {10.3390/ph15020159},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255197},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}
@article{UmstaetterDomhanHertleinetal.2020,
  author    = {Umst{\"a}tter, Florian and Domhan, Cornelius and Hertlein, Tobias and Ohlsen, Knut and M{\"u}hlberg, Eric and Kleist, Christian and Zimmermann, Stefan and Beijer, Barbro and Klika, Karel D. and Haberkorn, Uwe and Mier, Walter and Uhl, Philipp},
  title     = {Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides},
  series = {Angewandte Chemie International Edition},
  volume    = {59},
  journal   = {Angewandte Chemie International Edition},
  number    = {23},
  doi       = {10.1002/anie.202002727},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215550},
  pages     = {8823 -- 8827},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}