Thiazolylaminomannosides As Potent Antiadhesives of Type 1 Piliated Escherichia coli Isolated from Crohn鈥檚 Disease Patients

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• 作者：Sami Brument ; Adeline Sivignon ; Tetiana I. Dumych ; Nicolas Moreau ; Goedele Roos ; Yann Gu茅rardel ; Thibaut Chalopin ; David Deniaud ; Rostyslav O. Bilyy ; Arlette Darfeuille-Michaud ; Julie Bouckaert ; S茅bastien G. Gouin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5395-5406
• 全文大小：596K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

Adherent-invasive Escherichia coli (AIEC) have previously been shown to induce gut inflammation in patients with Crohn鈥檚 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 10000-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 antiadhesive potential. Given the key role of AIEC in the chronic intestinal inflammation of CD patients, these results suggest a potential antiadhesive treatment with the FimH inhibitors developed.