Targeting sialic acid catabolism with polyvalent sialidase inhibitors to mitigate bacterial inflammation in the gut
Year: 2025
Type: article
Abstract: Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic inflammatory disorders strongly associated with intestinal dysbiosis and the overgrowth of pro-inflammatory Enterobacteriaceae . A key driver of this imbalance is microbial mucin degradation, which liberates sialic acids that in turn fuel the expansion of pathogenic bacteria. Inhibiting sialic acid catabolism therefore represents a promising anti-virulence strategy to restore intestinal homeostasis. In this study, we designed and synthesized (neo)glycopolymers bearing sialic acid analogues as polyvalent inhibitors of bacterial sialidases and sialate O -acetylesterases (SIAE), the enzymes responsible for cleaving sialic acids and removing O -acetyl groups from acetylated sialic acids coating protective mucins. Three glycopolymers were developed, incorporating either a non-hydrolyzable free thiosialoside motif, a C-9 acetylated thiosialoside motif, or a transition-state analogue (poly-S-Neu5Ac2en 100 ). These polymeric inhibitors exhibited strong multivalent effects, with poly-S-Neu5Ac2en 100 achieving subnanomolar potency against the Bacteroides sialidases Bt SA and Bv SA, far exceeding the efficacy of their monovalent counterparts. Functional assays revealed that poly-S-Neu5Ac2en 100 effectively blocked mucin desialylation and strongly suppressed the growth of adherent-invasive Escherichia coli (AIEC), a pathobiont frequently linked to Crohn's disease. However, preliminary in vivo experiments in a murine colitis model did not yield robust improvements in disease activity, likely reflecting the limitations of adequately reproducing chronic disease in this model. Overall, our findings establish polyvalent sialidase inhibitors as exceptionally potent blockers of bacterial sialidases and valuable chemical tools to probe the role of sialic acid metabolism in dysbiosis.
Source: Bioorganic Chemistry
Authors: Mélyne Baudin Marie, Zoé Oblette, Mathieu Scalabrini, Denis Loquet, Devon W. Kavanaugh, David Deniaud, Thomas Bessonnet, Nizar Amzil, Aziz Elgarrab, Cyrille Grandjean, Clément Gonnot, Fabien Boeda, Laurent Fontaine, Véronique Montembault, Franck Daligault, Nicolas Barnich, Adeline Sivignon, Sébastien G. Gouin
Institutions: Centre National de la Recherche Scientifique, Chimie et Interdisciplinarité, Synthèse, Analyse, Modélisation, Nantes Université, Inserm, Université Clermont Auvergne, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Microbe, Intestine, Inflammation and Host Susceptibility, Unité en Sciences Biologiques et Biotechnologies de Nantes, Le Mans Université, Institut des Molécules et Matériaux du Mans
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,240
Funders: Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Conseil National de la Recherche Scientifique, Université Clermont-Auvergne, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, CHIST-ERA
OpenAlex ID: W4416530252