Targeting sialic acid catabolism with polyvalent sialidase inhibitors to mitigate bacterial inflammation in the gut

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-Neu5Ac2en₁₀₀). These polymeric inhibitors exhibited strong multivalent effects, with poly-S-Neu5Ac2en₁₀₀ achieving subnanomolar potency against the Bacteroides sialidases BtSA and BvSA, far exceeding the efficacy of their monovalent counterparts. Functional assays revealed that poly-S-Neu5Ac2en₁₀₀ 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.