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Structures of C-mannosylated anti-adhesives bound to the type 1 fimbrial FimH adhesin.

ABSTRACT: Selective inhibitors of the type 1 fimbrial adhesin FimH are recognized as attractive alternatives for antibiotic therapies and prophylaxes against Escherichia coli infections such as urinary-tract infections. To construct these inhibitors, the ?-d-mannopyranoside of high-mannose N-glycans, recognized with exclusive specificity on glycoprotein receptors by FimH, forms the basal structure. A hydrophobic aglycon is then linked to the mannose by the O1 oxygen inherently present in the ?-anomeric configuration. Substitution of this O atom by a carbon introduces a C-glycosidic bond, which may enhance the therapeutic potential of such compounds owing to the inability of enzymes to degrade C-glycosidic bonds. Here, the first crystal structures of the E. coli FimH adhesin in complex with C-glycosidically linked mannopyranosides are presented. These findings explain the role of the spacer in positioning biphenyl ligands for interactions by means of aromatic stacking in the tyrosine gate of FimH and how the normally hydrated C-glycosidic link is tolerated. As these new compounds can bind FimH, it can be assumed that they have the potential to serve as potent new antagonists of FimH, paving the way for the design of a new family of anti-adhesive compounds against urinary-tract infections.

SUBMITTER: de Ruyck J

PROVIDER: S-EPMC4856138 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Structures of C-mannosylated anti-adhesives bound to the type 1 fimbrial FimH adhesin.

de Ruyck Jerome J Lensink Marc F MF Bouckaert Julie J

IUCrJ 20160226 Pt 3

Selective inhibitors of the type 1 fimbrial adhesin FimH are recognized as attractive alternatives for antibiotic therapies and prophylaxes against Escherichia coli infections such as urinary-tract infections. To construct these inhibitors, the α-d-mannopyranoside of high-mannose N-glycans, recognized with exclusive specificity on glycoprotein receptors by FimH, forms the basal structure. A hydrophobic aglycon is then linked to the mannose by the O1 oxygen inherently present in the α-anomeric co ...[more]

PMID: 27158502

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Project description:We recently reported that the type 1-fimbriated Escherichia coli strains CSH-50 and HB101(pPKL4), both K-12 derivatives, have different patterns of adhesion to yeast mannan, human plasma fibronectin, and fibronectin derivatives, suggesting functional heterogeneity of type 1 fimbriae. In this report, we provide evidence that this functional heterogeneity is due to variations in the fimH genes. We also investigated functional heterogeneity among clinical isolates and whether variation in fimH genes accounts for differences in receptor specificity. Twelve isolates obtained from human urine were tested for their ability to adhere to mannan, fibronectin, periodate-treated fibronectin, and a synthetic peptide copying the 30 amino-terminal residues of fibronectin. CSH-50 and HB101(pPKL4) were tested for comparison. Selected isolates were also tested for adhesion to purified fragments spanning the entire fibronectin molecule. Three distinct functional classes, designated M, MF, and MFP, were observed. The fimH genes were amplified by PCR from chromosomal DNA obtained from representative strains and expressed in a delta fim strain (AAEC191A) transformed with a recombinant plasmid containing the entire fim gene cluster but with a translational stop-linker inserted into the fimH gene (pPKL114). Cloned fimH genes conferred on AAEC191A(pPKL114) receptor specificities mimicking those of the parent strains from which the fimH genes were obtained, demonstrating that the FimH subunits are responsible for the functional heterogeneity. Representative fimH genes were sequenced, and the deduced amino acid sequences were compared with the previously published FimH sequence. Allelic variants exhibiting >98% homology and encoding proteins differing by as little as a single amino acid substitution confer distinct adhesive phenotypes. This unexpected adhesive diversity within the FimH family broadens the scope of potential receptors for enterobacterial adhesion and may lead to a fundamental change in our understanding of the role(s) that type 1 fimbriae may play in enterobacterial ecology or pathogenesis.

Project description:Escherichia coli strains adhere to the normally sterile human uroepithelium using type 1 pili, that are long, hairy surface organelles exposing a mannose-binding FimH adhesin at the tip. A small percentage of adhered bacteria can successfully invade bladder cells, presumably via pathways mediated by the high-mannosylated uroplakin-Ia and alpha3beta1 integrins found throughout the uroepithelium. Invaded bacteria replicate and mature into dense, biofilm-like inclusions in preparation of fluxing and of infection of neighbouring cells, being the major cause of the troublesome recurrent urinary tract infections.We demonstrate that alpha-D-mannose based inhibitors of FimH not only block bacterial adhesion on uroepithelial cells but also antagonize invasion and biofilm formation. Heptyl alpha-D-mannose prevents binding of type 1-piliated E. coli to the human bladder cell line 5637 and reduces both adhesion and invasion of the UTI89 cystitis isolate instilled in mouse bladder via catheterization. Heptyl alpha-D-mannose also specifically inhibited biofilm formation at micromolar concentrations. The structural basis of the great inhibitory potential of alkyl and aryl alpha-D-mannosides was elucidated in the crystal structure of the FimH receptor-binding domain in complex with oligomannose-3. FimH interacts with Man alpha1,3Man beta1,4GlcNAc beta1,4GlcNAc in an extended binding site. The interactions along the alpha1,3 glycosidic bond and the first beta1,4 linkage to the chitobiose unit are conserved with those of FimH with butyl alpha-D-mannose. The strong stacking of the central mannose with the aromatic ring of Tyr48 is congruent with the high affinity found for synthetic inhibitors in which this mannose is substituted for by an aromatic group.The potential of ligand-based design of antagonists of urinary tract infections is ruled by the structural mimicry of natural epitopes and extends into blocking of bacterial invasion, intracellular growth and capacity to fluxing and of recurrence of the infection.

Dataset Information

Structures of C-mannosylated anti-adhesives bound to the type 1 fimbrial FimH adhesin.

Publications

Structures of C-mannosylated anti-adhesives bound to the type 1 fimbrial FimH adhesin.

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