Synthesis of structure-defined β-1,4-GlcNAc-modified wall teichoic acids as potential vaccine against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a high priority pathogen due to its life-threating infections to human health. Development of prophylactic or therapeutic anti-MRSA vaccine is a potential approach to treat S. aureus infections and overcome the resistance crisis. β -1,4-GlcNAc glycosylated wall teichoic acids (WTAs) derived from S. aureus are a new type of antigen that is closely associated with β-lactam resistance. In this study, structure-defined β -1,4-GlcNAc-modified WTAs varied in chain length and numbers of GlcNAc modification were synthesized by an ionic liquid-supported oligosaccharide synthesis (ILSOS) strategy in high efficiency and chromatography-free approach. Then the obtained WTAs were conjugated with tetanus toxin (TT) as vaccine candidates and were further evaluated in a mouse model to determine the structure-immunogenicity relationship. In vivo immunological studies revealed that the WTAs-TT conjugates provoked robust T cell-dependent responses and elicited high levels of specific anti-WTAs IgG antibodies production associated with the WTAs structure including chain length as well as the β -1,4-GlcNAc modification pattern. Heptamer WTAs conjugate T6 , carrying three copy of β -1,4-GlcNAc modified RboP, was identified to elicit the highest titers of specific antibody production. The T6 antisera exhibited the highest recognition and binding affinity and the most potent OP-killing activities to MSSA and MRSA cells. This study demonstrated that β -1,4-GlcNAc glycosylated WTAs are promising antigens for further development against MRSA. Structure-defined β -1,4-GlcNAc-modified WTA vaccines elicited robust immune responses and the specific IgG antibodies could recognize and display significant opsonophagocytic activity to methicillin-resistant Staphylococcus aureus. [Display omitted] • ILs supported strategy is developed to synthesize β -1,4-GlcNAc modified WTAs in rapid and cost-effective approach. • Glycosylated WTAs-TT conjugates are prepared as vaccine candidates to investigate the structure-immunogenicity relationship. • WTAs length and the β-1,4-GlcNAc modification pattern affect the immune responses and anti-WTAs antibodies production. • Conjugate T6 induces the highest IgG production and displays the most potent OPK against methicillin-resistant S. aureus. [ABSTRACT FROM AUTHOR]