Glycodendrimers as Anti-Adhesion Drugs Against Type 1 Fimbriated E. coli Uropathogenic Infections

Abstract

Bacterial drug resistance against antimicrobial agents is a prevalent and central worldwide impasse. Infections with resistant organisms lead to adverse clinical outcomes, increased mortality, and are costly to healthcare systems. Several infectious diseases are initiated by the binding of pathogenic lectins to host cells glycoconjugates. The molecular understanding of these adhesion phenomena is crucial and presents promising new alternatives compared to traditional antibiotic therapies. Glycans or glycan mimetics could be used to inhibit the initial recognition events leading to adhesion and colonization of host tissues by pathogens. The bladder and urothelial lining are widely covered by cell surface glycoproteins bearing the required carbohydrate ligands responsible for the adhesion phenomena. However, when these interactions are measured on a per saccharide basis, they are generally too weak (mM) for the design of beneficial inhibition therapies. The interactions between microbial pathogens and host cells are often governed by polyvalent and overall strong avidities. To overcome this drawback, glycobiologists have design a new family of well-defined small macromolecules, called glycodendrimers that can successfully address this issue. This review will provide a brief introduction on glycodendrimers and detailed descriptions of design and applications of mannosylated inhibitors against fimbriated type 1 E. coli.

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

“…These results, obtained with multivalent glycomimetics as ligands of FimH and as inhibitors of type 1 fimbriae-mediated adhesion of E. coli, [32,33,43] are not in accordance with the monovalent nature of the fimbrial lectin, though. In addition, clustering of several FimH CRDs by typical multivalent glycomimetics is unlikely, given the size of fimbriae and their distance dimensions on the bacterial surface.…”

“…Their synthesis and testing results as inhibitors of UPEC has recently been reviewed in detail. [43] Mannose Glycoclusters with Noncarbohydrate Core…”

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

“…This knowledge can be utilized when FimH antagonists are designed. 7,11 In addition, mannopyranosides with a rather extended aglycon moiety have often shown enhanced binding affinity, [18][19][20] but in this case no conclusive interpretation of structure-activity relationships has been achieved. 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.…”

Glycomimetics and Glycodendrimers as High Affinity Microbial Anti‐adhesins

“…[34] Amongst these, the early hyperbranched l-lysine scaffold, prepared by solidphase peptide and Fmoc chemistry, was elongated with Nchloroacetylglycylglycine and efficiently coupled to an Nacryloylated para-aminophenyl a-d-mannopyranoside [35] to provide octamer 19 (IC 50 2.8 nm (22.4 nm/Man)) (Scheme 2). It was found that a competitive binding assay measuring the binding of 125 I-labeled, highly mannosylated neoglycoprotein (BSA) to the type 1 fimbriated Escherichia coli (K12) strain in suspension gave much lower IC 50 values than the equivalent values obtained by hemagglutination or in assays that [a] Relative potency for the inhibition of binding of E. coli to epithelial cells.…”