2. Academic Validation
  3. Discovery of potent 1,1-diarylthiogalactoside glycomimetic inhibitors of Pseudomonas aeruginosa LecA with antibiofilm properties

Discovery of potent 1,1-diarylthiogalactoside glycomimetic inhibitors of Pseudomonas aeruginosa LecA with antibiofilm properties

  • Eur J Med Chem. 2023 Feb 5;247:115025. doi: 10.1016/j.ejmech.2022.115025.
Alexandre Bruneau 1,  Emilie Gillon 2,  Aurélie Furiga 3,  Etienne Brachet 1,  Mouad Alami 1,  Christine Roques 3,  Annabelle Varrot 2,  Anne Imberty 4,  Samir Messaoudi 5
Affiliations

Affiliations

  • 1 BioCIS, Univ. Paris-Sud, CNRS, University Paris-Saclay, Châtenay-Malabry, France.
  • 2 Université Grenoble Alpes, CNRS, CERMAV, 38000, Grenoble, France.
  • 3 LCG, Laboratoire de Génie Chimique (UMR 5503), Département Bioprocédés et Systèmes Microbiens, Université de Toulouse, CNRS, INPT, UPS, Toulouse, France.
  • 4 Université Grenoble Alpes, CNRS, CERMAV, 38000, Grenoble, France. Electronic address: anne.imberty@cermav.cnrs.fr.
  • 5 BioCIS, Univ. Paris-Sud, CNRS, University Paris-Saclay, Châtenay-Malabry, France. Electronic address: samir.messaoudi@universite-paris-saclay.fr.
PMID: 36549118 DOI: 10.1016/j.ejmech.2022.115025
Abstract

In this work, β-thiogalactoside mimetics bearing 1,1-diarylmethylene or benzophenone aglycons have been prepared and assayed for their affinity towards LecA, a lectin and virulence factor from Pseudomonas aeruginosa involved in Bacterial adhesion and biofilm formation. The hit compound presents higher efficiency than previously described monovalent inhibitors and the crystal structure confirmed the occurrence of additional contacts between the aglycone and the protein surface. The highest affinity (160 nM) was obtained for a divalent ligand containing two galactosides. The monovalent high affinity compound (Kd = 1 μM) obtained through structure-activity relationship (SAR) showed efficient antibiofilm activity with no associated bactericidal activity.

Keywords

Antibiofilm activity; Pseudomonas aeruginosa; Structure-activity relationship; Thiogalactoside.

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