Synthetic β-(1→6)-Linked N-Acetylated and Nonacetylated Oligoglucosamines Used To Produce Conjugate Vaccines for Bacterial Pathogens

2009/12/01 by Marina L. Gening, Tomás Maira‐Litrán, Tomás Maira-Litrán +6 · 115 citations
Agricultural and Biological Sciences · Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Acinetobacter baumannii #Antibiotics #Antibody #Antigen #Bacteria #Biochemistry #Biology #Conjugate #Conjugate vaccine #Escherichia coli #Escherichia coli research studies #Immune Response and Inflammation #Immunization #Immunology #Microbiology #Probiotics and Fermented Foods #Pseudomonas aeruginosa #Staphylococcus aureus #Streptococcus pneumoniae #Toxoid #Virology #Virulence #Yersinia pestis

paper · open access · doi:10.1128/iai.01093-09

published in Infection and Immunity 78(2), 764-772 (American Society for Microbiology)

openalex publication_date 2009/12/01 · openalex created_date 2016/06/24 · openalex updated_date 2026/08/01

Abstract

Vaccines for pathogens usually target strain-specific surface antigens or toxins, and rarely is there broad antigenic specificity extending across multiple species. Protective antibodies for bacteria are usually specific for surface or capsular antigens. beta-(1-->6)-Poly-N-acetyl-d-glucosamine (PNAG) is a surface polysaccharide produced by many pathogens, including Staphylococcus aureus, Escherichia coli, Yersinia pestis, Bordetella pertussis, Acinetobacter baumannii, and others. Protective antibodies to PNAG are elicited when a deacetylated glycoform (deacetylated PNAG [dPNAG]; <30% acetate) is used in conjugate vaccines, whereas highly acetylated PNAG does not induce such antibodies. Chemical derivation of dPNAG from native PNAG is imprecise, so we synthesized both beta-(1-->6)-d-glucosamine (GlcNH(2)) and beta-(1-->6)-d-N-acetylglucosamine (GlcNAc) oligosaccharides with linkers on the reducing termini that could be activated to produce sulfhydryl groups for conjugation to bromoacetyl groups introduced onto carrier proteins. Synthetic 5-mer GlcNH(2) (5GlcNH(2)) or 9GlcNH(2) conjugated to tetanus toxoid (TT) elicited mouse antibodies that mediated opsonic killing of multiple S. aureus strains, while the antibodies that were produced in response to 5GlcNAc- or 9GlcNAc-TT did not mediate opsonic killing. Rabbit antibodies to 9GlcNH(2)-TT bound to PNAG and dPNAG antigens, mediated killing of S. aureus and E. coli, and protected against S. aureus skin abscesses and lethal E. coli peritonitis. Chemical synthesis of a series of oligoglucosamine ligands with defined differences in N acetylation allowed us to identify a conjugate vaccine formulation that generated protective immune responses to two of the most challenging bacterial pathogens. This vaccine could potentially be used to engender protective immunity to the broad range of pathogens that produce surface PNAG.

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• Current advances and challenges in the development of Acinetobacter vaccines. [europepmc]
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• The exceptionally broad-based potential of active and passive vaccination targeting the conserved microbial surface polysaccharide PNAG. [europepmc]
• The Effect of a BSA Conjugate of a Synthetic Hexasaccharide Related to the Fragment of Capsular Polysaccharide of Streptococcus pneumoniae Type 14 on the Activation of Innate and Adaptive Immune Responses. [europepmc]
• A semisynthetic Streptococcus pneumoniae serotype 8 glycoconjugate vaccine. [europepmc]
• Neoglycoconjugate of Tetrasaccharide Representing One Repeating Unit of the Streptococcus pneumoniae Type 14 Capsular Polysaccharide Induces the Production of Opsonizing IgG1 Antibodies and Possesses the Highest Protective Activity As Compared to Hexa- and Octasaccharide Conjugates. [europepmc]
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• Antibody to Poly-N-acetyl glucosamine provides protection against intracellular pathogens: Mechanism of action and validation in horse foals challenged with Rhodococcus equi. [europepmc]
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• Discovery of Semi- and Fully-Synthetic Carbohydrate Vaccines Against Bacterial Infections Using a Medicinal Chemistry Approach. [europepmc]
• Vaccine development to control the rising scourge of antibiotic-resistant Acinetobacter baumannii : a systematic review. [europepmc]
• Synthetic Glycans to Improve Current Glycoconjugate Vaccines and Fight Antimicrobial Resistance. [europepmc]
• Molecular Targets for Antibody-Based Anti-Biofilm Therapy in Infective Endocarditis. [europepmc]
• Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines. [europepmc]
• Polysaccharides' Structures and Functions in Biofilm Architecture of Antimicrobial-Resistant (AMR) Pathogens. [europepmc]
• Sugar-Coated: Can Multivalent Glycoconjugates Improve upon Nature's Design? [europepmc]

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