Chemical inhibition of sialic acid catabolism from gut microbiota, a therapeutic perspective against inflammatory bowel diseases – SIALOBACTER

Mucins are infections protective glycoproteins of the intestinal wall displaying on their surface sialic acids in important quantities such as N-acetylneuraminic acid (Neu5Ac) and its C-9 acetylated analogue (Neu5,9Ac2). Neu5Ac serves as a metabolic substrate for the development of specific bacterial species in the microbiota. Several independent studies show that an excessive hydrolysis of Neu5Ac by bacterial sialidases (SAs$) leads to an outburst of enterobacteria and especially Escherichia coli. This disturbed environment could favor the adherent and invasive Escherichia coli strains (AIEC). These AIEC are overrepresented in the gut of patients with Crohn's disease, and play a fundamental role in the severity of the inflammation. Interestingly, Neu5Ac catabolism is also indirectly triggered by bacterial sialate-O-acetylesterases (SIAE) such as EstA, an enzyme converting Neu5,9Ac2 from mucins to Neu5Ac substrates. Finally, a recent study also implicates human sialidase (Neu3) in these inflammatory processes (de-sialylation of the protective intestinal alkaline phosphatase). The SIALOBACTER project proposes for the first time to develop potent and selective multivalent inhibitors of these different enzyme families (SA, SIAE, Neu3). These compounds will allow to study more precisely their biological function, and will constitute an innovative approach for the treatment of chronic inflammatory bowel diseases by lowering the intestinal colonization level of AIEC.