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

Abstract

Adhesion is a prerequisite for bacteria to colonize cell surfaces. To accomplish cellular adhesion, many bacteria use carbohydrate‐specific lectins, which are expressed as part of capillary protein appendages expanding from their surface, called fimbriae or pili. For bacteria, colonization of cell surfaces offers advantageous conditions to persist and multiply. For the host, however, bacterial colonization can be affiliated with severe health problems such as inflammation. Therefore, to combat bacterial adhesion and inflammatory diseases, investigation of the molecular and biophysical details of the relevant lectin–carbohydrate interactions is important. Understanding molecular carbohydrate recognition can lead to the development of high‐affinity inhibitors of bacterial lectins. That way, interfering with the bacterial attachment to surfaces proves the vision of an antiadhesion therapy, among others, against uropathogenic E. coli (UPEC). One of the most important and best investigated bacterial lectins is the mannose‐specific protein FimH, which is expressed on the tips of type 1 fimbriae. During the last 30 years, many natural as well as synthetic mannosidic ligands of FimH have been designed and tested for their inhibitory potencies. We report key results and comment on key problems and perspectives of this research.

Inhibition of type 1 fimbriae-mediated Escherichia coli adhesion and biofilm formation by trimeric cluster thiomannosides conjugated to diamond nanoparticles

“…Indeed various O-glycoside-derived trimeric clusters have been shown to be strong ligands for FimH compared with their corresponding monovalent analogues. 20,28 Moreover, it has been demonstrated that trimeric mannoside and thiomannoside clusters, related to those proposed, often give relatively large multivalent effects towards mannose-specific lectins. [56][57][58][59][60] The sugar-linker of our 2 nd -generation ND-sugar conjugates is quite different from the one featured in the 1 st -generation NDs, (synthesized through the "clicking" of propargyl glycosides to ND-grafted azido functions) and would thus very probably make different secondary interactions with the sugar-binding pocket in FimH.…”

“…The plates were then incubated at room temperature for 15 min and again rinsed. The crystal violet was completely dissolved by addition of 150 µL of ethanol-acetone (80 : 20), and the OD 595 of the resulting solution was measured. The reported data are averages of three replicate wells in three independent experiments.…”

“…[14][15][16][17][18][19] Among the targets that have been identified for anti-adhesive nanoparticles are type 1 fimbriae, which constitute major virulence factors produced by Escherichia coli (E. coli). 20 Type 1 fimbriae are filamentous tubular structures each of 0.2-2.0 µm in length and 5-7 nm in diameter that are distributed over the entire surface of the bacterium. 21 In various E. coli strains the lectin located at the extremity of type 1 fimbriae, FimH, contributes to tissue colonization through its specific recognition of the terminal α-D-mannopyranosyl units present on cell-surface glycoproteins.…”

“…The types of multivalent structures targeting FimH thus far reported are very varied and range from small-to medium-sized scaffolds presenting carbohydrate-derived ligands, to larger entities such as sugar-decorated polymers and nanoparticles, and a multitude of creatively designed compounds in between. 20,38,39 We and others have been interested in exploring whether the reported characteristic properties of nanodiamonds (NDs) might be taken advantage of in the development of useful inhibitors of type 1 fimbriae-mediated E. coli adhesion. [40][41][42]72 ND particles are completely inert, optically transparent, biocompatible and moreover, easily functionalizable via a variety of strategies depending on their intended application.…”

Exploitation of Glycobiology in Anti-Adhesion Approaches against Biothreat Agents

“…For bacteria, fimbriae or pili are the typical organelles utilised during an initial attachment (Figure 1). In many cases, it is a monomeric lectin with only one binding site at the tip of the fimbriae that is the actual adhesin and the large number of these external structures on the bacterial surface generates multiple anchoring points [13]. Other type of pili can express multiple lectins on one organelle to provide multivalency by a 'Velcro® mechanism' [14].…”