Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease

ABSTRACT The ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia coli (AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Adeline Sivignon, Xibo Yan, Dimitri Alvarez Dorta, Richard Bonnet, Julie Bouckaert, Etienne Fleury, Julien Bernard, Sébastien G. Gouin, Arlette Darfeuille-Michaud, Nicolas Barnich
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1ef07e44bddd4567876566ae20c1d360
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1ef07e44bddd4567876566ae20c1d360
record_format	dspace
spelling	oai:doaj.org-article:1ef07e44bddd4567876566ae20c1d3602021-11-15T15:41:23ZDevelopment of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease10.1128/mBio.01298-152150-7511https://doaj.org/article/1ef07e44bddd4567876566ae20c1d3602015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01298-15https://doaj.org/toc/2150-7511ABSTRACT The ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia coli (AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists of FimH, the adhesin of type 1 pili, for their ability to block AIEC adhesion to intestinal epithelial cells (IEC). Monovalent and multivalent derivatives of n-heptyl α-d-mannoside (HM), a nanomolar antagonist of FimH, were tested in vitro in IEC infected with the AIEC LF82 strain and in vivo by oral administration to CEACAM6-expressing mice infected with LF82 bacteria. In vitro, multivalent derivatives were more potent than the monovalent derivatives, with a gain of efficacy superior to their valencies, probably owing to their ability to form bacterial aggregates. Of note, HM and the multi-HM glycoconjugates exhibited lower efficacy in vivo in decreasing LF82 gut colonization. Interestingly, HM analogues functionalized with an isopropylamide (1A-HM) or β-cyclodextrin pharmacophore at the end of the heptyl tail (1CD-HM) exerted beneficial effects in vivo. These two compounds strongly decreased the amount of LF82 bacteria in the feces of mice and that of bacteria associated with the gut mucosa when administered orally at a dose of 10 mg/kg of body weight after infection. Importantly, signs of colitis and intestinal inflammation induced by LF82 infection were also prevented. These results highlight the potential of the antiadhesive compounds to treat CD patients abnormally colonized by AIEC bacteria and point to an alternative to the current approach focusing on blocking proinflammatory mediators. IMPORTANCE Current treatments for Crohn's disease (CD), including immunosuppressive agents, anti-tumor necrosis factor alpha (anti-TNF-α) and anti-integrin antibodies, focus on the symptoms but not on the cause of the disease. Adherent-invasive Escherichia coli (AIEC) bacteria abnormally colonize the ileal mucosa of CD patients via the interaction of the mannose-specific adhesin FimH of type 1 pili with CEACAM6 mannosylated proteins expressed on the epithelial cell surface. Thus, we decided to develop an antiadhesive strategy based on synthetic FimH antagonists specifically targeting AIEC bacteria that would decrease intestinal inflammation. Heptylmannoside (HM)-based glycocompounds strongly inhibit AIEC adhesion to intestinal epithelial cells in vitro. The antiadhesive effect of two of these compounds of relatively simple chemical structure was also observed in vivo in AIEC-infected CEACAM6-expressing mice and was associated with a reduction in the signs of colitis. These results suggest a new therapeutic approach for CD patients colonized by AIEC bacteria, based on the development of synthetic FimH antagonists.Adeline SivignonXibo YanDimitri Alvarez DortaRichard BonnetJulie BouckaertEtienne FleuryJulien BernardSébastien G. GouinArlette Darfeuille-MichaudNicolas BarnichAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Adeline Sivignon Xibo Yan Dimitri Alvarez Dorta Richard Bonnet Julie Bouckaert Etienne Fleury Julien Bernard Sébastien G. Gouin Arlette Darfeuille-Michaud Nicolas Barnich Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease
description	ABSTRACT The ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia coli (AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists of FimH, the adhesin of type 1 pili, for their ability to block AIEC adhesion to intestinal epithelial cells (IEC). Monovalent and multivalent derivatives of n-heptyl α-d-mannoside (HM), a nanomolar antagonist of FimH, were tested in vitro in IEC infected with the AIEC LF82 strain and in vivo by oral administration to CEACAM6-expressing mice infected with LF82 bacteria. In vitro, multivalent derivatives were more potent than the monovalent derivatives, with a gain of efficacy superior to their valencies, probably owing to their ability to form bacterial aggregates. Of note, HM and the multi-HM glycoconjugates exhibited lower efficacy in vivo in decreasing LF82 gut colonization. Interestingly, HM analogues functionalized with an isopropylamide (1A-HM) or β-cyclodextrin pharmacophore at the end of the heptyl tail (1CD-HM) exerted beneficial effects in vivo. These two compounds strongly decreased the amount of LF82 bacteria in the feces of mice and that of bacteria associated with the gut mucosa when administered orally at a dose of 10 mg/kg of body weight after infection. Importantly, signs of colitis and intestinal inflammation induced by LF82 infection were also prevented. These results highlight the potential of the antiadhesive compounds to treat CD patients abnormally colonized by AIEC bacteria and point to an alternative to the current approach focusing on blocking proinflammatory mediators. IMPORTANCE Current treatments for Crohn's disease (CD), including immunosuppressive agents, anti-tumor necrosis factor alpha (anti-TNF-α) and anti-integrin antibodies, focus on the symptoms but not on the cause of the disease. Adherent-invasive Escherichia coli (AIEC) bacteria abnormally colonize the ileal mucosa of CD patients via the interaction of the mannose-specific adhesin FimH of type 1 pili with CEACAM6 mannosylated proteins expressed on the epithelial cell surface. Thus, we decided to develop an antiadhesive strategy based on synthetic FimH antagonists specifically targeting AIEC bacteria that would decrease intestinal inflammation. Heptylmannoside (HM)-based glycocompounds strongly inhibit AIEC adhesion to intestinal epithelial cells in vitro. The antiadhesive effect of two of these compounds of relatively simple chemical structure was also observed in vivo in AIEC-infected CEACAM6-expressing mice and was associated with a reduction in the signs of colitis. These results suggest a new therapeutic approach for CD patients colonized by AIEC bacteria, based on the development of synthetic FimH antagonists.
format	article
author	Adeline Sivignon Xibo Yan Dimitri Alvarez Dorta Richard Bonnet Julie Bouckaert Etienne Fleury Julien Bernard Sébastien G. Gouin Arlette Darfeuille-Michaud Nicolas Barnich
author_facet	Adeline Sivignon Xibo Yan Dimitri Alvarez Dorta Richard Bonnet Julie Bouckaert Etienne Fleury Julien Bernard Sébastien G. Gouin Arlette Darfeuille-Michaud Nicolas Barnich
author_sort	Adeline Sivignon
title	Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease
title_short	Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease
title_full	Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease
title_fullStr	Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease
title_full_unstemmed	Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease
title_sort	development of heptylmannoside-based glycoconjugate antiadhesive compounds against adherent-invasive <named-content content-type="genus-species">escherichia coli</named-content> bacteria associated with crohn's disease
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/1ef07e44bddd4567876566ae20c1d360
work_keys_str_mv	AT adelinesivignon developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT xiboyan developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT dimitrialvarezdorta developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT richardbonnet developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT juliebouckaert developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT etiennefleury developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT julienbernard developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT sebastienggouin developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT arlettedarfeuillemichaud developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease AT nicolasbarnich developmentofheptylmannosidebasedglycoconjugateantiadhesivecompoundsagainstadherentinvasivenamedcontentcontenttypegenusspeciesescherichiacolinamedcontentbacteriaassociatedwithcrohnsdisease
_version_	1718427691745542144

Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive <named-content content-type="genus-species">Escherichia coli</named-content> Bacteria Associated with Crohn's Disease

Ejemplares similares