Mannose Presenting ‘Glyco-Colicins’ Convert the Bacterial Cell Surface into a Multivalent Adsorption Site for Adherent Bacteria

Biofilm formation is integral to the pathogenesis of numerous adherent bacteria and contributes to antimicrobial resistance (AMR). The rising threat of AMR means the need to develop novel non-bactericidal anti-adhesion approaches against such bacteria is more urgent than ever. Both adherent invasive Eschericia coli (AIEC, implicated in inflammatory bowel disease) and uropathogenic E. coli (UPEC, responsible for ~80% of urinary tract infections) adhere to terminal mannose sugars on epithelial glycoproteins through the FimH adhesin on their type 1 pilus. Although mannose-based inhibitors have previously been explored to inhibit binding of adherent bacteria to epithelial cells, this approach has been limited by monovalent carbohydrate-protein interactions. Herein we pioneer a novel approach to this problem through the preparation of colicin E9 bioconjugates that bind to the abundant BtuB receptor in the outer membrane of bacteria, enabling multivalent presentation of functional motifs on the cell surface. We show these bioconjugates label the surface of live E. coli, and furthermore demonstrate that mannose presenting “glyco-colicins” induce E. coli aggregation, using the bacteria itself as a multivalent platform for mannose display which triggers binding to adjacent FimH presenting bacteria.