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Carbohydrates as Drugs pp 123–168Cite as

Discovery and Application of FimH Antagonists

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Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 12))

Abstract

Just like bacteria need to be mobile to seek for nutrients, bacteria need to adhere to biotic and abiotic surfaces to enable their progression. Most bacteria regulate the expression of a multitude of fimbrial adhesins that display varying specificities and architectures. FimH at the tip of type 1 fimbriae is one of the first recognized lectins on Escherichia coli. FimH evokes through its binding symptomatic and chronic E. coli infections in the urinary tract, in the intestine, and beyond. The mannose specificity of type 1 fimbriae has been the lead to the discovery of the FimH adhesin more than 32 years ago and presents today a role model as the template for anti-adhesive drug design. Curiously, the specificity of the FimH lectin had been defined very early on toward a Manα1,3Manβ1,4GlcNAc trisaccharide isolated from the urine of mannosidase-deficient patients. Indeed, a much larger dependence of bacterial adhesion can be attributed to structural differences in the mannosidic receptors than based on amino acid variance in FimH. The crystal structure of FimH in complex with oligomannoside-3 presented a breakthrough that enhanced the rational design of mannose-based anti-adhesives against FimH. In this overview, we will provide insights gained from a plethora of FimH antagonists. Crystal structures of FimH in complex with anti-adhesives and applications in vivo in mouse models for metabolic diseases reveal unexpected features and alternative routes for improved molecules.

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Abbreviations

AIEC:

Adherent-invasive E. coli

ATP:

Adenosine triphosphate

bpMan:

Biphenyl α- d-mannose

BM:

Butyl α- d-mannose

cAMP:

Cyclic adenosine monophosphate

CDK2:

Cyclin dependent kinase 2

CEACAM6:

Carcinoembryonic antigen-related cell adhesion molecule 6

CRP:

cAMP receptor protein

DC-SIGN:

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin

DFT:

Density functional theory

DP:

Degree of polymerization

E. coli :

Escherichia coli

ER:

Endoplasmic reticulum

ESI-MS:

Electrospray ionization mass spectrometry

GPI:

Glycosylphosphatidylinositol

HDAC6:

Histone deacetylase 6

HM:

Heptyl α- d-mannose

HSA:

Human serum albumin

IBC:

Intracellular bacterial community

ITC:

Isothermal titration calorimetry

LB:

Luria Bertani

M cells:

Microfold cells, these are cells found in the follicle-associated epithelium of the Peyer’s patch

MD:

Molecular dynamics

MM:

Methyl α- d-mannose

MO:

Molecular orbital

NMR:

Nuclear magnetic resonance

PDB:

Protein data bank

RR:

Recurrency rate

SAXS:

Small-angle X-ray solution scattering

SPR:

Surface plasmon resonance

SQM:

Semi-empirical quantum mechanical

TazMan:

Thiazolyl α- d-mannose

TNF-α:

Tumor necrosis factor alpha

UTI:

Urinary tract infection

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Authors and Affiliations

  1. Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation (CEISAM), LUNAM Université, UMR 6230 du CNRS, 2, rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France

    Sébastien G. Gouin

  2. VUB department of General Chemistry and VIB department of Structural Biology, Vrije Universiteit Brussel, VIB, Building G, Pleinlaan 2, 1050, Brussels, Belgium

    Goedele Roos

  3. Unité de Glycobiologie Structurale et Fonctionnelle, Université Lille 1, UMR 8576 du CNRS, Avenue Mendeleiev building C9, 59655, Villeneuve d’Ascq, France

    Julie Bouckaert

Authors
  1. Sébastien G. Gouin
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  2. Goedele Roos
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  3. Julie Bouckaert
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Correspondence to Julie Bouckaert .

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  1. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

    Peter H. Seeberger

  2. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

    Christoph Rademacher

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Gouin, S.G., Roos, G., Bouckaert, J. (2014). Discovery and Application of FimH Antagonists. In: Seeberger, P., Rademacher, C. (eds) Carbohydrates as Drugs. Topics in Medicinal Chemistry, vol 12. Springer, Cham. https://doi.org/10.1007/7355_2014_52

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