title: An antibacterial vaccination strategy based on a glycoconjugate containing the core lipopolysaccharide tetrasaccharide Hep2Kdo2.
abstract: Certain non-mammalian cell wall sugars are conserved across a variety of pathogenic bacteria. This conservation of structure, combined with their structural differences when compared with mammalian sugars, make them potentially powerful epitopes for immunization. Here, we report the synthesis of a glycoconjugate that displays the so-called 'inner core' sugars of Gram-negative bacterial cell walls. We also describe an antibacterial vaccination strategy based on immunization with the glycoconjugate and the subsequent administration of an inhibitor that uncovers the corresponding epitope in pathogenic bacteria. The core tetrasaccharide, Hep2Kdo2, a common motif in bacterial lipopolysaccharides, was synthesized and attached via a chain linker to a diphtheria toxin mutant carrier protein. This glycoconjugate generated titres of antibodies towards the inner core tetrasaccharide of the lipopolysaccharide, which were capable of binding the cell-surface sugars of bacterial pathogenic strains including Neisseria meningitidis, Pseudomonas aeruginosa and Escherichia coli. Exposure of bacterial lipopolysaccharide in in vitro experiments, using an inhibitor of capsular polysaccharide transport, enabled potent bacterial killing with antiserum.
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Lingbing
authors.initials: L
authors.lastname: Kong
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Balakumar
authors.initials: B
authors.lastname: Vijayakrishnan
authors.affiliation: GlycoVaxyn AG, Grabenstrasse 3, Schlieren 8952, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Kowarik
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Jin
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Zakharova
authors.affiliation: GlycoVaxyn AG, Grabenstrasse 3, Schlieren 8952, Switzerland.
authors.forename: Larissa
authors.initials: L
authors.lastname: Neiwert
authors.affiliation: GlycoVaxyn AG, Grabenstrasse 3, Schlieren 8952, Switzerland.
authors.forename: Amirreza
authors.initials: A
authors.lastname: Faridmoayer
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Davis
mesh_terms: D001428:Bacterial Vaccines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004167:Diphtheria Toxin / Q000737:chemistry; D006001:Glycoconjugates / Q000737:chemistry* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000378:metabolism; D050296:Microbial Viability / Q000187:drug effects*; D009345:Neisseria meningitidis / Q000187:drug effects / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism
chemical_list: D001428:Bacterial Vaccines; D004167:Diphtheria Toxin; D006001:Glycoconjugates; D008070:Lipopolysaccharides