J Med Chem. 2013 Jul 11;56(13):5395-406.

Thiazolylaminomannosides as potent anti-adhesives of type 1 piliated Escherichia coli isolated from Crohn’s disease patients.

Sami Brument,Adeline Sivignon,‡a Tetiana I. Dumych,I Nicolas Moreau, Goedele Roos,” Yann Guérardel, Thibaut Chalopin, David Deniaud, Rostyslav O. Bilyy,I* Arlette Darfeuille-Michaud,‡a,b* Julie Bouckaert,* Sébastien G. Gouin*

† LUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 NANTES Cedex 3, France.

‡ Clermont Université, UMR 1071 Inserm/Université d’Auvergne, 63000 Clermont-Ferrand, France

a INRA, Unité Sous Contrat 2018, 63000 Clermont-Ferrand, France

b Centre Hospitalier Universitaire, 63000 Clermont-Ferrand, France

I Institute of Cell Biology, NationalAcademy of Sciences of Ukraine, Lviv, Ukraine,

” Algemene Chemie (ALGC), Vrije Universiteit Brussel, Brussels, Belgium,

Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), UMR8576 du CNRS, Université Lille 1, F-59655 Villeneuve d’Ascq Cedex, France.



Adherent-Invasive Escherichia coli (AIEC), which colonize the ileal mucosa of patients with CD, adhere to and invade intestinal epithelial cells with Crohn’s disease (CD). We developed a set of mannosides to prevent AIEC attachment to the gut by blocking the FimH bacterial adhesin. The crystal structure of the FimH lectin domain in complex with a lead thiazolylaminomannoside highlighted the preferential position for pharmacomodulations. A small library of analogues showing nanomolar affinity for FimH was then developed. Notably, AIEC attachment to intestinal cells was efficiently prevented by the most active compound and at around 10,000-fold and 100-fold lower concentrations than mannose and the potent FimH inhibitor heptylmannoside, respectively. An ex vivo assay performed on the colonic tissue of a transgenic mouse model of CD confirmed this anti-adhesive potential. Given the key role of AIEC adhesion/invasion of intestinal epithelial cells in CD patients, these results suggest a potential anti-adhesive treatment with the FimH inhibitors developed.



Crohn’s disease (CD) is a lifelong chronic disease which affects 4 millions of people worldwide with a prevalence of about 100 cases per 100,000 individuals. The ileal microbiota of CD patients is shifted due to an overexpression of carcinoembryonic antigen–related cell adhesion molecule 6 (CEACAM6). CEACAM6 presents oligomannosides on the surface allowing adherent-invasive E. coli (AIEC) to bind to the intestinal cells via the fimbrial adhesin (FimH). This overgrowth of E. coli can result from host-mediated inflammation and further abnormal expression of molecules acting as receptors for bacterial adhesion. Marketed CD drugs suppress the inflammatory response by lowering TNF levels.

We recently hypothesized that going right to the source, and targeting the CD-causing bacteria rather than the inflammatory response could provide a valuable alternative therapy. The concept is based on inhibiting and removing the attachment of AIEC to the gut by preventing the FimH bacterial adhesin to bind to the CEACAM6 receptor overexpressed at the surface of intestinal cells from CD patients (Figure 1).

 Rostyslav BilyyFigure 1- Alternative strategy proposed to treat CD. Antiadhesive drugs are used for blocking pathogenic bacteria binding to intestinal cells.


We developed a chemical cyclocondensation to graft heterocyclic compounds in the anomeric position of mannosides, with the aim to further interact with the so-called “tyrosine gate” at the entrance of the FimH binding site (Figure 2).  Among the heterocyclic mannosides developed, a thiazolylaminomannoside (Tazman 1) was identified as a promising hit compound and a crystal structure with Tazman 1 bound to FimH receptor-binding domain was obtained. Pharmacomodulations were performed and a much stronger inhibitor was identified. Lead Tazman 2 was shown to be around 10000-fold and 100-fold more potent than mannose and heptyl α-d-mannoside (a nanomolar FimH inhibitor) in preventing AIEC attachment to intestinal cells. An ex vivo assay performed on the colonic tissue of a transgenic mouse model of CD confirmed its anti-adhesive potential.


Rostyslav Bilyy fig2Figure 2- General strategy leading to the potent anti-adhesive compound 2. Given the key role played by AIEC in maintaining the chronic ileal inflammation in patients, our results suggest the potential of these FimH inhibitors in alternative treatments and combination therapies of Crohn’s disease.

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