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

Eva Zahorska (1, 2) , Francesca Rosato (3) , Kai Stober (3) , Sakonwan Kuhaudomlarp (4) , Joscha Meiers (1, 2) , Dirk Hauck (1, 2) , Dorina Reith (3) , Emilie Gillon (4) , Katharina Rox (5) , Anne Imberty (4) , Winfried Römer (3) , Alexander Titz (1, 2)

1 HZI - Helmholtz-Zentrum für Infektionsforschung GmbH
2 Universität des Saarlandes [Saarbrücken]
3 Albert-Ludwigs-Universität Freiburg
4 CERMAV - Centre de Recherches sur les Macromolécules Végétales
5 HZI - Helmholtz Centre for Infection Research

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 5000-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.

Domaines: Chimie thérapeutique

Eva Zahorska, Francesca Rosato, Kai Stober, Sakonwan Kuhaudomlarp, Joscha Meiers, et al.. Neutralizing the Impact of the Virulence Factor LecA from Pseudomonas aeruginosa on Human Cells with New Glycomimetic Inhibitors. Angewandte Chemie International Edition, 2023, 62 (7), pp.e202215535. ⟨10.1002/anie.202215535⟩. ⟨hal-03908729⟩