Abstract
Adherent-invasive Escherichia coli (AIEC) have previously been shown to induce gut inflammation in patients 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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adhesins, Escherichia coli / metabolism
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Bacterial Adhesion / drug effects*
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Binding Sites
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Caco-2 Cells
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism
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Colon / drug effects
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Colon / metabolism
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Colon / microbiology
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Crohn Disease / microbiology*
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Escherichia coli / metabolism
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Escherichia coli / physiology*
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Fimbriae Proteins / antagonists & inhibitors
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Fimbriae Proteins / metabolism
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Fimbriae, Bacterial / physiology
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GPI-Linked Proteins / genetics
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GPI-Linked Proteins / metabolism
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Host-Pathogen Interactions / drug effects
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Humans
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Intestines / drug effects
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Intestines / microbiology
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Jurkat Cells
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Mannosides / chemical synthesis
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Mannosides / chemistry
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Mannosides / pharmacology*
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Mice
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Mice, Transgenic
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Models, Chemical
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Molecular Structure
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Thiazoles / chemical synthesis
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Thiazoles / chemistry
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Thiazoles / pharmacology
Substances
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Adhesins, Escherichia coli
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Antigens, CD
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CEACAM6 protein, human
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Cell Adhesion Molecules
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GPI-Linked Proteins
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Mannosides
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Thiazoles
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fimH protein, E coli
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Fimbriae Proteins