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Neutralizing the Impact of the Virulence Factor LecA from Pseudomonas aeruginosa on Human Cells with New Glycomimetic Inhibitors.

  • Zahorska, Eva1, 2, 3
  • Rosato, Francesca4, 5
  • Stober, Kai4, 5
  • Kuhaudomlarp, Sakonwan6, 7, 8
  • Meiers, Joscha1, 2, 3
  • Hauck, Dirk1, 2, 3
  • Reith, Dorina4, 5
  • Gillon, Emilie6
  • Rox, Katharina3, 9
  • Imberty, Anne6
  • Römer, Winfried4, 5, 10
  • Titz, Alexander1, 2, 3
  • 1 Chemical Biology of Carbohydrates (CBCH), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123, Saarbrücken, Germany. , (Germany)
  • 2 Department of Chemistry, Saarland University, 66123, Saarbrücken, Germany. , (Germany)
  • 3 Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-, Braunschweig, Germany. , (Germany)
  • 4 Faculty of Biology, University of Freiburg, 79104, Freiburg, Germany. , (Germany)
  • 5 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104, Freiburg, Germany. , (Germany)
  • 6 Université Grenoble Alpes, CNRS, CERMAV, 38000, Grenoble, France. , (France)
  • 7 Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand. , (Thailand)
  • 8 Center for Excellence in Protein and Enzyme Technology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand. , (Thailand)
  • 9 Department of Chemical Biology (CBIO), Helmholtz Centre for Infection Research (HZI), 38124, Braunschweig, Germany. , (Germany)
  • 10 Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104, Freiburg, Germany. , (Germany)
Published Article
Angewandte Chemie International Edition in English
Wiley (John Wiley & Sons)
Publication Date
Feb 06, 2023
DOI: 10.1002/anie.202215535
PMID: 36398566


Bacterial adhesion, biofilm formation and host cell invasion of the ESKAPE pathogen Pseudomonas aeruginosa require the tetravalent lectins LecA and LecB, which are therefore drug targets to fight these infections. Recently, we have reported highly potent divalent galactosides as specific LecA inhibitors. However, they suffered from very low solubility and an intrinsic chemical instability due to two acylhydrazone motifs, which precluded further biological evaluation. Here, we isosterically substituted the acylhydrazones and systematically varied linker identity and length between the two galactosides necessary for LecA binding. The optimized divalent LecA ligands showed improved stability and were up to 1000-fold more soluble. Importantly, these properties now enabled their biological characterization. The lead compound L2 potently inhibited LecA binding to lung epithelial cells, restored wound closure in a scratch assay and reduced the invasiveness of P. aeruginosa into host cells. © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

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