Oligomannoside mimetics by glycosylation of ‘octopus glycosides’ and their investigation as inhibitors of type 1 fimbriae-mediated adhesion of Escherichia coli

Abstract

The glycocalyx of eukaryotic cells is composed of glycoconjugates, which carry highly complex oligosaccharide portions. To elucidate the biological role and function of the glycocalyx in cell-cell communication and cellular adhesion processes, glycomimetics have become targets of glycosciences, which resemble the composition and structural complexity of the glycocalyx constituents. Here, we report about the synthesis of a class of oligosaccharide mimetics of a high-mannose type, which were obtained by mannosylation of spacered mono- and oligosaccharide cores. These carbohydrate-centered cluster mannosides have been targeted as inhibitors of mannose-specific bacterial adhesion, which is mediated by so-called type 1 fimbriae. Their inhibitory potencies were measured by ELISA and compared to methyl mannoside as well as to a series of mannobiosides, and finally to the polysaccharide mannan. The obtained results suggest a new interpretation of the mechanisms of bacterial adhesion according to a macromolecular rather than a multivalency effect.

The Bacterial Lectin FimH, a Target for Drug Discovery – Carbohydrate Inhibitors of Type 1 Fimbriae‐Mediated Bacterial Adhesion

“…In 2006, very similar saccharides were investigated as inhibitors of the adhesion of type 1 fimbriated E. coli to mannan in an enzymelinked immunosorbent assay (ELISA). [26] Lindhorst and co-workers employed allyl mannobiosides Manα1,2Manα1-OAll (5), Manα1,3Manα1-OAll (6), Manα1,6Manα1-OAll (7) and Manα1,4Manα1-OAll (8), and the allyl trimannoside Manα1,6[Manα1,3]Man1α-OAll (9), and largely found relative inhibitory potencies similar to those reported by Ofek and his colleagues. However, the α1,3-linked disaccharide 6 performed significantly better in the ELISA, giving a RIP value of 11 ( Figure 2).…”

“…Multivalent glycopolymers, [39][40][41][42] for example, might interact with a lectin according to fundamentally different models than a multivalent glycocluster, which is based on a carbohydrate core, for instance. [26] Among multivalent glycomimetics, glycodendrimers are an especially promising class of molecules, which have been evaluated as antiadhesives. Their synthesis and testing results as inhibitors of UPEC has recently been reviewed in detail.…”

“…However, it was also shown that the way an α-mannosyl ligand is scaffolded on a particular oligosaccharide is crucial. While for trisaccharide 10, Manα1,3Manβ1,4GlcNAc, a RIP value of 21 was determined, its isomer 11, Manα1,6Manβ1,4GlcNAc, had [25] [b] values from inhibition of adhesion of type 1 fimbriated E. coli HB101 pPKL4 to the polysaccharide mannan, measured by ELISA; [26] [c] "Oligomannose-9 and -3" are named according to a suggestion made in the literature, [28] where they were tested as ligands for the fimbrial lectin FimH (vide infra).…”

Exploitation of Glycobiology in Anti-Adhesion Approaches against Biothreat Agents

“…Exciting examples of multivalent glycoconjugates inhibiting type 1 fimbriae-mediated bacterial adhesion include Octopus glycosides, tetravalent glycocluster based on azamacrocycles, glycodendrimers and hexavalent thiourea-based glycocluster, bifunctional ligands and glyconanodiamonds [28][29][30][31]. Adhesion on multivalent glycomaterials and glyconanodiamonds decorated with mannose can be utilized for aggregating E. coli and removing them from polluted water [13].…”

Conformationally Mobile Glucosylthioureidocalix[6]- and Calix[8]arenes: Synthesis, Aggregation and Lectin Binding

“…the phenomenon of multivalency [9,10] frequently associated with the recognition of these substrates have boosted the design and synthesis of a wide range of polyglycosylated compounds [11][12][13][14][15][16][17]. The major aim is to clarify the principles [10,18] of the so-called glycoside cluster effect [19] and find new bioactive molecules for diagnostic [20] and therapy [21][22][23] based on the saccharide recognition.…”