Neutralizing the Impact of the Virulence Factor LecA from Pseudomonas aeruginosa on Human Cells with New Glycomimetic Inhibitors.
Glycomimetics
Lectin
Pathoblocker
Pseudomonas Aeruginosa
Virulence
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
06 02 2023
06 02 2023
Historique:
received:
21
10
2022
pubmed:
19
11
2022
medline:
7
2
2023
entrez:
18
11
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36398566
doi: 10.1002/anie.202215535
pmc: PMC10107299
doi:
Substances chimiques
Adhesins, Bacterial
0
Virulence Factors
0
Galactosides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202215535Informations de copyright
© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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