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

In this work, beta-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 mu M) obtained through structureactivity relationship (SAR) showed efficient antibiofilm activity with no associated bactericidal activity.

Automated summary

In this study, beta-thiogalactoside mimetics bearing 1,1-diarylmethylene or benzophenone aglycons were synthesized and tested for their affinity towards LecA. The hit compound showed higher efficiency and additional contacts with the protein surface were confirmed by crystal structure. The highest affinity was observed for a divalent ligand containing two galactosides. The monovalent high affinity compound obtained through structure-activity relationship (SAR) displayed effective antibiofilm activity without bactericidal activity.