Linear and cyclic oligo-β-(1→6)-D-glucosamines: Synthesis, conformations, and applications for design of a vaccine and oligodentate glycoconjugates

Poly-β-(1 → 6)-N-acetyl-D-glucosamine is an exopolysaccharide secreted by numerous pathogenic bacteria, including Staphylococcus aureus, Escherichia coli, Yersinia pestis, Bordetella pertussis, Acinetobacter baumannii, Burkholderia spp., and others. A con- vergent approach was developed for the synthesis of oligosaccharide fragments consisting of 5, 7, 9, and 11 glucosamine or N-acetylglucosamine units and for the preparation of five nona-β-(1 → 6)-D-glucosamines with various N-acetylation patterns. Penta- and nona- β-(1 → 6)-D-glucosamines conjugated to protein carriers through a specially developed sulfhydryl linker proved to be highly immunogenic in mice and rabbits and elicited antibod- ies that mediated opsonic killing of multiple strains of S. aureus (including methicillin-resist- ant S. aureus, MRSA) and E. coli, and protected against S. aureus skin abscesses and lethal E. coli and B. cenocepacia peritonitis. These findings provide a basis for the construction of a unique semisynthetic vaccine against multiple bacterial targets. Conformational studies by means of special NMR experiments and computer model- ing revealed that the oligo-β-(1 → 6)-D-glucosamine chain exists mostly in a helix-like con- formation, where the terminal monosaccharides are arranged close to each other. Owing to