An antibacterial vaccination strategy based on a glycoconjugate containing the core lipopolysaccharide tetrasaccharide Hep2Kdo2

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 g...

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Veröffentlicht in:Nature chemistry 2016-03, Vol.8 (3), p.242-249
Hauptverfasser: Kong, Lingbing, Vijayakrishnan, Balakumar, Kowarik, Michael, Park, Jin, Zakharova, Alexandra N., Neiwert, Larissa, Faridmoayer, Amirreza, Davis, Benjamin G.
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Sprache:eng
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Zusammenfassung: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, Hep 2 Kdo 2 , 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. The presence and linkage of unusual higher sugars in the ‘inner core’ of Gram-negative bacteria makes the core lipopolysacchride tetrasaccharide Hep 2 Kdo 2 a tough target. Now, a 2+2 glycosylation strategy has facilitated the synthesis of this glycoconjugate. Synthesis of Hep 2 Kdo 2 enabled 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.
ISSN:1755-4330
1755-4349
DOI:10.1038/nchem.2432