@article{RubioCosialsSchulzLambertsenetal.2018,
  author    = {Rubio-Cosials, Anna and Schulz, Eike C. and Lambertsen, Lotte and Smyshlyaev, Georgy and Rojas-Cordova, Carlos and Forslund, Kristoffer and Karaca, Ezgi and Bebel, Aleksandra and Bork, Peer and Barabas, Orsolya},
  title     = {Transposase-DNA Complex Structures Reveal Mechanisms for Conjugative Transposition of Antibiotic Resistance},
  series = {Cell},
  volume    = {173},
  journal   = {Cell},
  number    = {1},
  doi       = {10.1016/j.cell.2018.02.032},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227085},
  pages     = {e20, 208-220},
  year      = {2018},
  abstract  = {Conjugative transposition drives the emergence of multidrug resistance in diverse bacterial pathogens, yet the mechanisms are poorly characterized. The Tn1549 conjugative transposon propagates resistance to the antibiotic vancomycin used for severe drug-resistant infections. Here, we present four high-resolution structures of the conserved Y-transposase of Tn1549 complexed with circular transposon DNA intermediates. The structures reveal individual transposition steps and explain how specific DNA distortion and cleavage mechanisms enable DNA strand exchange with an absolute minimum homology requirement. This appears to uniquely allow Tn916-like conjugative transposons to bypass DNA homology and insert into diverse genomic sites, expanding gene transfer. We further uncover a structural regulatory mechanism that prevents premature cleavage of the transposon DNA before a suitable target DNA is found and generate a peptide antagonist that interferes with the transposase-DNA structure to block transposition. Our results reveal mechanistic principles of conjugative transposition that could help control the spread of antibiotic resistance genes.},
  language  = {en}
}
@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}
}