Issue 40, 2013

Aromatic thioglycoside inhibitors against the virulence factor LecA from Pseudomonas aeruginosa

Abstract

Three small families of hydrolytically stable thioaryl glycosides were prepared as inhibitors of the LecA (PA-IL) virulence factor corresponding to the carbohydrate binding lectin from the bacterial pathogen Pseudomonas aeruginosa. The monosaccharidic arylthio β-D-galactopyranosides served as a common template for the major series that was also substituted at the O-3 position. Arylthio disaccharides from lactose and from melibiose constituted the other two series members. In spite of the fact that the natural ligand for LecA is a glycolipid of the globotriaosylceramide having an α-D-galactopyranoside epitope, this study illustrated that the β-D-galactopyranoside configuration having a hydrophobic aglycon could override the requirement toward the anomeric configuration of the natural sugar. The enzyme linked lectin assay together with isothermal titration microcalorimetry established that naphthyl 1-thio-β-D-galactopyranoside (11) gave the best inhibition with an IC50 twenty-three times better than that of the reference methyl α-D-galactopyranoside. In addition it showed a KD of 6.3 μM which was ten times better than that of the reference compound. The X-ray crystal structure of LecA with 11 was also obtained.

Graphical abstract: Aromatic thioglycoside inhibitors against the virulence factor LecA from Pseudomonas aeruginosa

Supplementary files

Article information

Article type
Paper
Submitted
10 Jul 2013
Accepted
12 Aug 2013
First published
10 Sep 2013

Org. Biomol. Chem., 2013,11, 6906-6918

Aromatic thioglycoside inhibitors against the virulence factor LecA from Pseudomonas aeruginosa

J. Rodrigue, G. Ganne, B. Blanchard, C. Saucier, D. Giguère, T. C. Shiao, A. Varrot, A. Imberty and R. Roy, Org. Biomol. Chem., 2013, 11, 6906 DOI: 10.1039/C3OB41422A

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