|
|||||
|
|
Neutralizing the Impact of the Virulence Factor LecA from Pseudomonas aeruginosa on Human Cells with New Glycomimetic Inhibitors |
|
| Authors: | Eva Zahorska Francesca Rosato Kai Stober Sakonwan Kuhaudomlarp Joscha Meiers Dirk Hauck Dorina Reith Emilie Gillon Katharina Rox Anne Imberty Winfried Römer Alexander Titz |
| Institution: | 1. Chemical Biology of Carbohydrates (CBCH), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123 Saarbrücken, Germany;2. Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany;3. Université Grenoble Alpes, CNRS, CERMAV, 38000 Grenoble, France;4. Chemical Biology of Carbohydrates (CBCH), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123 Saarbrücken, Germany
Department of Chemistry, Saarland University, 66123 Saarbrücken, Germany Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-, Braunschweig, Germany;5. Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany;6. Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-, Braunschweig, Germany |
| Abstract: | 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. |
| Keywords: | Glycomimetics Lectin Pathoblocker Pseudomonas Aeruginosa Virulence |