Structural basis for the interaction between human milk oligosaccharides and the bacterial lectin PA-IIL of Pseudomonas aeruginosa

Abstract

One of the mechanisms contributing to the protection by breast-feeding of the newborn against enteric diseases is related to the ability of human milk oligosaccharides to prevent the attachment of pathogenic bacteria to the duodenual epithelium. Indeed, a variety of fucosylated oligosaccharides, specific to human milk, form part of the innate immune system. In the present study, we demonstrate the specific blocking of PA-IIL, a fucose-binding lectin of the human pathogen Pseudomonas aeruginosa, by milk oligosaccharides. Two fucosylated epitopes, Lewis a and 3-fucosyl-lactose (Lewis x glucose analogue) bind to the lectin with dissociation constants of 2.2x10(-7) M and 3.6x10(-7) M respectively. Thermodynamic studies indicate that these interactions are dominated by enthalpy. The entropy contribution is slightly favourable when binding to fucose and to the highest-affinity ligand, Lewis a. The high-resolution X-ray structures of two complexes of PA-IIL with milk oligosaccharides allow the precise determination of the conformation of a trisaccharide and a pentasaccharide. The different types of interaction between the oligosaccharides and the protein involve not only hydrogen bonding, but also calcium- and water-bridged contacts, allowing a rationalization of the thermodynamic data. This study provides important structural information about compounds that could be of general application in new therapeutic strategies against bacterial infections.

Honey and royal jelly, like human milk, abrogate lectin-dependent infection-preceding Pseudomonas aeruginosa adhesion

“…The groups of Imberty and Wimmerova endorsed our results by elucidating the 3-dimensional crystallographic and thermodynamic interactions of that lectin with the fucosylated lewis a (Le a ) receptor (which mediates P. aeruginosa binding to the lungs of cystic fibrosis patients) and with the competing milk saccharides (Mitchell et al, 2002;Perret et al, 2005).…”

Role of LecA and LecB Lectins in Pseudomonas aeruginosa -Induced Lung Injury and Effect of Carbohydrate Ligands

“…LecA is a D-galactose-binding lectin with high affinity for terminal glycans presenting an ␣-galactose residue at the nonreducing end (4,18). The LecB lectin has a high affinity for L-fucose and its derivatives (24,35). Several studies have suggested that blockade or inhibition of these lectins by specific carbohydrates may be useful for prevention and treatment of P. aeruginosa infections (28,31).…”

Glycopeptide dendrimers as Pseudomonas aeruginosa biofilm inhibitors

“…The critical role of L-fucose was evidenced by the absence of lectin binding to the control N-acetylated dendrimer library. A selection of hit sequences were resynthesized and their lectin binding characterized in detail by ELLA, 51 which identified hit FD2 as the most potent ligand with an IC 50 = 11 mM towards lectin UEA-I and a relative potency of 115 in reference to L-fucose, corresponding to a six-fold affinity enhancement per fucosyl group. Although the multivalency effect observed with FD2 was modest, it was confirmed by the observation of much weaker binding in the divalent and monovalent glycopeptide analogs of the dendrimer.…”