Cluster Mannosides as Inhibitors of Type 1 Fimbriae-Mediated Adhesion ofEscherichia coli: Pentaerythritol Derivatives as Scaffolds

Abstract

Pentaerythritol derivatives were used as core molecules for the synthesis of two cluster α-D-mannosides, which were designed as oligomannoside mimetics. The problem of glycosyl orthoester formation, which frequently occurs in oligo-mannosylations, was solved. The clusters were tested for their

Inhibition of Adhesion of Type 1 Fimbriated Escherichia coli to Highly Mannosylated Ligands

“…For example, the IC 50 value of Me a-Man in our study was 10 mM, while that reported by Firon et al [18] using a yeast agglutination assay was around 0.3 mM, and that determined by an ELISA with yeast mannan coated plates was 2.5 ± 4 mM. [15,17] As mentioned in the Results section, because of generally much lower IC 50 values obtained in our assay, we were also able to determine or estimate the IC 50 values of some very poor inhibitors. For instance, Me a-Glc, the 2-epimer of Me aMan, had 10 4 -fold lower affinity than Me a-Man, suggesting that the axial 2-OH group of Man is a very important element in the binding by the adhesin.…”

“…Assays used most often by others are based on E. coli mediated yeast or erythrocyte agglutination [16,18] or ELISAs with microtiter wells coated with yeast mannan. [14,15] In both of these methods, the binding of bacteria to ligand involves a highly clustered network of potential ligand residues, so that the binding of bacteria is perhaps not freely reversible, and an inhibitor would not have a fair chance of competing. In our assay, the tagged ligand was a Man-containing neoglycoprotein, which contained a large number of Man-bearing chains, each chain terminating in a single residue of a-mannose.…”

“…Preparation of a number of multivalent mannosides of different structural designs and their inhibitory potencies have been reported. [14,15,17] The enhancement in inhibition potency of these cluster mannosides with two to eight Man residues linked by the ordinary O-glycosidic linkage ranged from 10-to 250-fold over Me a-Man. However, since the nature of aglycon greatly influences the binding affinity of type 1 E. coli adhesin, the true affinity enhancement by these cluster mannosides is difficult to assess.…”

Bi- and trivalent glycopeptide mannopyranosides as inhibitors of type 1 fimbriae-mediated bacterial adhesion: variation of valency, aglycon and scaffolding

“…The same is true for multivalency effects that have frequently been observed with miscellaneous cluster mannopyranosides as ligands for type 1 fimbriated bacteria, especially with bi-and trivalent glycoclusters. [21][22][23][24][25] A possible explanation, why multivalent mannopyranosides perform well as inhibitors of FimH, can be found in a statistical effect (basically an elevated local mannoside concentration), 26 on the other hand, it has been speculated that secondary binding sites on the fimbrial lectin might be occupied by multivalent mannnosides, hence resulting in an increased affinity of such ligands. 27 On this account, a number of open questions about carbohydrate recognition of type 1 fimbriated E. coli bacteria have formed the basis of a study, in which bi-and trivalent low-molecular weight glycopeptides have been synthesized and tested as inhibitors of type 1 fimbriae-mediated bacterial adhesion to a mannancoated surface.…”

Unique tetrameric and hexameric mannoside clusters prepared by click chemistry

“…23 In particular, those derived from mannose have been synthesized and investigated as inhibitors of bacterial adhesion by different research groups. [24][25][26][27][28][29][30][31][32][33][34][35][36][37] We aim to expand the repertoire of available polyvalent mannosides in order to determine which scaffolds are most compatible with the FimH environment. We have chosen to use linker arms matching the heptyl glycoside that binds well to FimH 10,12 as others have done with different scoffolds.…”