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

Eva Zahorska; Francesca Rosato; Kai Stober; Sakonwan Kuhaudomlarp; Joscha Meiers; Dirk Hauck; Dorina Reith; Emilie Gillon; Katharina Rox; Anne Imberty; Winfried Römer; Alexander Titz

doi:10.1002/anie.202215535

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

Authors

Zahorska, Eva^{1, 2, 3}
Rosato, Francesca^{4, 5}
Stober, Kai^{4, 5}
Kuhaudomlarp, Sakonwan^{6, 7, 8}
Meiers, Joscha^{1, 2, 3}
Hauck, Dirk^{1, 2, 3}
Reith, Dorina^{4, 5}
Gillon, Emilie⁶
Rox, Katharina^{3, 9}
Imberty, Anne⁶
Römer, Winfried^{4, 5, 10}
Titz, Alexander^{1, 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)

Type

Published Article

Journal

Angewandte Chemie International Edition in English

Publisher

Wiley (John Wiley & Sons)

Publication Date

Feb 06, 2023

Volume

62

Issue

7

Identifiers

DOI: 10.1002/anie.202215535

PMID: 36398566

Source

Medline

Keywords

Language

English

License

Unknown

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. © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. This record was last updated on 04/28/2023 and may not reflect the most current and accurate biomedical/scientific data available from NLM. The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/36398566

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