Show legend Show as text

Structure type: homopolymer
Compound class: K-antigen, CPS
Contained glycoepitopes: IEDB_141807,IEDB_150077,IEDB_151531,IEDB_1711617

• Article ID: 3364
  Nikolaev AV, Botvinko IV, Ross AJ "Natural phosphoglycans containing glycosyl phosphate units: structural diversity and chemical synthesis" - Carbohydrate Research 342(3-4) (2007) 297-344
  

  An anomeric phosphodiester linkage formed by a glycosyl phosphate unit and a hydroxyl group of another monosaccharide is found in many glycopolymers of the outer membrane in bacteria (e.g., capsular polysaccharides and lipopolysaccharides), yeasts and protozoa. The polymers (phosphoglycans) composed of glycosyl phosphate (or oligoglycosyl phosphate) repeating units could be chemically classified as poly(glycosyl phosphates). Their importance as immunologically active components of the cell wall and/or capsule of numerous microorganisms upholds the need to develop routes for the chemical preparation of these biopolymers. In this paper, we (1) present a review of the primary structures (known to date) of natural phosphoglycans from various sources, which contain glycosyl phosphate units, and (2) discuss different approaches and recent achievements in the synthesis of glycosyl phosphosaccharides and poly(glycosyl phosphates).

  synthesis, structure, polysaccharides, Phosphoglycans, Anomeric phosphodiesters

  NCBI PubMed ID: 17092493
  Publication DOI: 10.1016/j.carres.2006.10.006
  Journal NLM ID: 0043535
  Publisher: Elsevier
  Correspondence: a.v.nikolaev@dundee.ac.uk
  Institutions: College of Life Sciences, Division of Biological Chemistry and Molecular Microbiology, University of Dundee, Dundee DD1 5EH, UK.
  
   
  
  Neisseria meningitidis X
  CSDB ID 21768 (all data & tools)
• Article ID: 4430
  Ovodov YS "Bacterial capsular antigens. Structural patterns of capsular antigens" - Biochemistry (Moscow) 71(9) (2006) 937-954
  

  Structural patterns of bacterial capsular antigens including capsular polysaccharides and exoglycans are given in this review. In addition, the immunological activity of capsular antigens and their role in type specificity of bacteria are discussed.

  structure, capsular polysaccharides, bacterial capsular antigens, bacterial exoglycans, immunological activity, type specificity

  NCBI PubMed ID: 17009947
  Publication DOI: 10.1134/S000629790609001X
  Journal NLM ID: 0376536
  Publisher: Nauka/Interperiodica
  Correspondence: ovoys@physiol.komisc.ru
  Institutions: Institute of Physiology, Komi Science Center, Urals Branch of the Russian Academy of Sciences, Syktyvkar 167982, Russia
  
   
  
  Neisseria meningitidis X
  CSDB ID 28787 (all data & tools)
• Article ID: 4639
  Willis LM, Whitfield C "Structure, biosynthesis, and function of bacterial capsular polysaccharides synthesized by ABC transporter-dependent pathways" - Carbohydrate Research 378 (2013) 35-44
  

  Bacterial capsules are formed primarily from long-chain polysaccharides with repeat-unit structures. A given bacterial species can produce a range of capsular polysaccharides (CPSs) with different structures and these help distinguish isolates by serotyping, as is the case with Escherichia coli K antigens. Capsules are important virulence factors for many pathogens and this review focuses on CPSs synthesized via ATP-binding cassette (ABC) transporter-dependent processes in Gram-negative bacteria. Bacteria utilizing this pathway are often associated with urinary tract infections, septicemia, and meningitis, and E. coli and Neisseria meningitidis provide well-studied examples. CPSs from ABC transporter-dependent pathways are synthesized at the cytoplasmic face of the inner membrane through the concerted action of glycosyltransferases before being exported across the inner membrane and translocated to the cell surface. A hallmark of these CPSs is a conserved reducing terminal glycolipid composed of phosphatidylglycerol and a poly-3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) linker. Recent discovery of the structure of this conserved lipid terminus provides new insights into the early steps in CPS biosynthesis.

  biosynthesis, capsular polysaccharides, glycosyltransferases, gram negative bacteria, export, ABC transporters

  NCBI PubMed ID: 23746650
  Publication DOI: 10.1016/j.carres.2013.05.007
  Journal NLM ID: 0043535
  Publisher: Elsevier
  Correspondence: C. Whitfield
  Institutions: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada N1G 2W1
  
   
  
  Neisseria meningitidis X
  CSDB ID 29825 (all data & tools)
• Article ID: 4835
  Berti F, Ravenscroft N "Characterization of Carbohydrate Vaccines by NMR Spectroscopy" - Methods in Molecular Biology 1331 (2015) 189-209
  

  Physicochemical techniques are a powerful tool for the structural characterization of carbohydrate-based vaccines. High-field Nuclear Magnetic Resonance (NMR) spectroscopy has been established as an extremely useful and robust method for tracking the industrial manufacturing process of these vaccines from polysaccharide bulk antigen through to the final formulation. Here, we describe the use of proton NMR for structural identity and conformity testing of carbohydrate-based vaccines.

  carbohydrates, capsular polysaccharide, antigens, nuclear magnetic resonance spectroscopy, vaccines

  NCBI PubMed ID: 26169742
  Publication DOI: 10.1007/978-1-4939-2874-3_12
  Journal NLM ID: 9214969
  Publisher: Springer
  Correspondence: francesco.x.berti@gsk.com
  Institutions: Research, GSK Vaccines, Via Fiorentina 1, 53100, Siena, Italy
  
   
  
  Neisseria meningitidis X
  CSDB ID 11092 (all data & tools)
• Article ID: 4867
  Tzeng YL, Thomas J, Stephens DS "Regulation of capsule in Neisseria meningitidis" - Critical Reviews in Microbiology 42(5) (2016) 759-772
  

  Neisseria meningitidis, a devastating pathogen exclusive to humans, expresses capsular polysaccharides that are the major meningococcal virulence determinants and the basis for successful meningococcal vaccines. With rare exceptions, the expression of capsule (serogroups A, B, C, W, X, Y) is required for systemic invasive meningococcal disease. Changes in capsule expression or structure (e.g. hypo- or hyper-encapsulation, capsule 'switching', acetylation) can influence immunologic diagnostic assays or lead to immune escape. The loss or down-regulation of capsule is also critical in meningococcal biology facilitating meningococcal attachment, microcolony formation and the carriage state at human mucosal surfaces. Encapsulated meningococci contain a cps locus with promoters located in an intergenic region between the biosynthesis and the conserved capsule transport operons. The cps intergenic region is transcriptionally regulated (and thus the amount of capsule expressed) by IS element insertion, by a two-component system, MisR/MisS and through sequence changes that result in post-transcriptional RNA thermoregulation. Reversible on-off phase variation of capsule expression is controlled by slipped strand mispairing of homo-polymeric tracts and by precise insertion and excision of IS elements (e.g. IS1301) in the biosynthesis operon. Capsule structure can be altered by phase-variable expression of capsular polymer modification enzymes or 'switched' through transformation and homologous recombination of different polymerases. Understanding the complex regulation of meningococcal capsule has important implications for meningococcal biology, pathogenesis, diagnostics, current and future vaccine development and vaccine strategies.

  Neisseria meningitidis, capsular polysaccharide, Bacterial virulence regulation, capsule switching, meningococcal diseases

  NCBI PubMed ID: 26089023
  Publication DOI: 10.3109/1040841X.2015.1022507
  Journal NLM ID: 8914274
  Publisher: CRC Press
  Correspondence: dstep01@emory.edu
  Institutions: Department of Medicine, Emory University School of Medicine, Woodruff Health Sciences Center, Atlanta, GA, USA
  
   
  
  Neisseria meningitidis X
  CSDB ID 11213 (all data & tools)
• Article ID: 5015
  Kuttel MM, Timol Z, Ravenscroft N "Cross-protection in Neisseria meningitidis serogroups Y and W polysaccharides: A comparative conformational analysis" - Carbohydrate Research (2017) 40-47
  

  The capsular polysaccharide is the main virulence factor in meningococcus. The capsular polysaccharides for meningococcal serogroups Y and W are almost identical polymers of hexose-sialic acid, suggesting the possibility of cross-protection between group Y and W vaccines. However, early studies indicated that they elicit different levels of cross-protection. Here we explore the conformations of the meningococcal Y and W polysaccharides with molecular dynamics simulations of three repeating unit oligosaccharide strands. We find differences in Y and W antigen conformation: the Y polysaccharide has a single dominant conformation, whereas W exhibits a family of conformations including the Y conformation. This result is supported by our NMR NOESY analysis, which indicates key close contacts for W that are not present in Y. These conformational differences provide an explanation for the different levels of cross-protection measured for the Y and W monovalent vaccines and the high group W responses observed in HibMenCY-TT vaccinees.

  molecular modelling, Meningococcus, Neisseria meningitidis, capsular polysaccharide, carbohydrate antigens, cross-protection, molecular dynamics simulation

  NCBI PubMed ID: 28501716
  Publication DOI: 10.1016/j.carres.2017.05.004
  Journal NLM ID: 0043535
  Publisher: Elsevier
  Correspondence: mkuttel@cs.uct.ac.za
  Institutions: Department of Computer Science, University of Cape Town, Cape Town, 7701, South Africa
  Methods: 13C NMR, 1H NMR, NMR-2D, conformation analysis, MD simulations, de-O-acetylation
  
   
  
  Neisseria meningitidis X
  CSDB ID 12152 (all data & tools)
• Article ID: 5129
  Berti F, De Ricco R, Rappuoli R "Role of O-Acetylation in the Immunogenicity of Bacterial Polysaccharide Vaccines" - Molecules 23(6) (2018) 1340
  

  The incidence of infectious diseases caused by several bacterial pathogens such as Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis, has been dramatically reduced over the last 25 years through the use of glycoconjugate vaccines. The structures of the bacterial capsular polysaccharide (CPS) antigens, extracted and purified from microbial cultures and obtained with very high purity, show that many of them are decorated by O-acetyl groups. While these groups are often considered important for the structural identity of the polysaccharides, they play a major role in the functional immune response to some vaccines such as meningococcal serogroup A and Salmonella typhi Vi, but do not seem to be important for many others, such as meningococcal serogroups C, W, Y, and type III Group B Streptococcus. This review discusses the O-acetylation status of CPSs and its role in the immunological responses of these antigens.

  O-acetylation, Bacterial polysaccharide, conjugate vaccines, Bacterial Vaccines, carbohydrate antigens

  NCBI PubMed ID: 29865239
  Publication DOI: 10.3390/molecules23061340
  Journal NLM ID: 100964009
  Publisher: Basel, Switzerland: MDPI
  Correspondence: rino.x.rappuoli@gsk.com
  Institutions: External R&D, GSK Vaccines, 53100 Siena, Italy, External R&D, GSK Vaccines, 53100 Siena, Ital
  
   
  
  Neisseria meningitidis X
  CSDB ID 13035 (all data & tools)
• Article ID: 5154
  Fiebig T, Litschko C, Freiberger F, Bethe A, Berger M, Gerardy-Schahn R "Efficient solid-phase synthesis of meningococcal capsular oligosaccharides enables simple and fast chemoenzymatic vaccine production" - Journal of Biological Chemistry 293(3) (2018) 953-962
  

  Neisseria meningitidis serogroups A and X are among the leading causes of bacterial meningitis in the African meningitis belt. Glycoconjugate vaccines, consisting of an antigenic carrier protein coupled to the capsular polysaccharide of the bacterial pathogen, are the most effective strategy for prevention of meningococcal disease. However, the distribution of effective glycoconjugate vaccines in this region is limited by the high cost of cultivating pathogens and purification of their capsular polysaccharides. Moreover, chemical approaches to synthesize oligosaccharide antigens have proven challenging. In the current study, we present a chemoenzymatic approach for generating tailored oligosaccharide fractions ready for activation and coupling to the carrier protein. In a first step, the elongation modes of recombinant capsular polymerases from Neisseria meningitidis serogroups A (CsaB) and X (CsxA) were characterized. We observed that CsaB is a distributive enzyme, and CsxA is a processive enzyme. Sequence comparison of these two stealth family proteins revealed a C-terminal extension in CsxA, which conferred processivity because of the existence of a second product-binding site. Deletion of the C-terminal domain converted CsxA into a distributive enzyme, allowing facile control of product length by adjusting the ratio of donor to acceptor sugars. Solid-phase fixation of the engineered capsular polymerases enabled rapid production of capsular polysaccharides with high yield and purity. In summary, the tools developed here provide critical steps toward reducing the cost of conjugate vaccine production, which will increase access in regions with the greatest need. Our work also facilitates efforts to study the relationship between oligosaccharide size and antigenicity.

  Neisseria meningitidis, polysaccharide, biotechnology, glycoconjugate, vaccine development, protein engineering, polymerase, solid-phase synthesis, hexose-phosphate transferase, stealth

  NCBI PubMed ID: 29187601
  Publication DOI: 10.1074/jbc.RA117.000488
  Journal NLM ID: 2985121R
  Publisher: Baltimore, MD: American Society for Biochemistry and Molecular Biology
  Correspondence: gerardy-schahn.rita@mh-hannover.de
  Institutions: Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany
  Methods: SDS-PAGE, genetic methods, immunoblotting, cloning, SEC, HPLC-AEC, solid-phase synthesis
  
   
  
  Neisseria meningitidis X
  CSDB ID 12561 (all data & tools)
• Article ID: 5161
  Hlozek J, Kuttel MM, Ravenscroft N "Conformations of Neisseria meningitidis serogroup A and X polysaccharides: The effects of chain length and O-acetylation" - Carbohydrate Research 465 (2018) 44-51
  

  Neisseria meningitidis is a major cause of bacterial meningitis worldwide especially in Africa. The capsular polysaccharide (CPS) is the main virulence factor and the target antigen for polysaccharide and conjugate vaccines. The high burden of serogroup A disease in the Meningitis Belt of sub-Saharan Africa led to the introduction of MenAfriVac®, which has successfully reduced the number of cases of group A disease. However, several outbreaks caused by other serogroups have been reported, including those due to serogroup X. The capsular polysaccharides of serogroups A and X are both homopolymers of amino sugars (?-D-ManNAc and ?-D-GlcNAc) containing phosphodiester linkages at C-6 and C-4, respectively. The similarity of the primary structures of the two polysaccharides suggests that serogroup A vaccination may provide cross-protection against serogroup X disease. Molecular dynamics simulations of a series of serogroup A and X oligosaccharides reveal that the MenA CPS behaves as a flexible random coil which becomes less conformationally defined as the length increases, whereas serogroup X forms a more stable regular helical structure. The presence of the MenX helix is supported by NMR analysis; it has four residues per turn and becomes more stable as the chain length increases. Licensed MenA vaccines are largely O-acetylated at C-3: simulations show that these O-acetyl groups are highly solvent exposed and their presence favors more extended conformations compared to the more compact conformations of MenA without O-acetylation. These findings may have implications for the design of optimal conjugate vaccines.

  Neisseria meningitidis, capsular polysaccharide, molecular modeling, Antigen conformation

  NCBI PubMed ID: 29940397
  Publication DOI: 10.1016/j.carres.2018.06.007
  Journal NLM ID: 0043535
  Publisher: Elsevier
  Correspondence: neil.ravenscroft@uct.ac.za
  Institutions: Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa, Department of Computer Science, University of Cape Town, Rondebosch, 7701, South Africa
  Methods: conformation analysis, MD simulations, post-simulation analysis
  
   
  
  Neisseria meningitidis X
  CSDB ID 12611 (all data & tools)
• Article ID: 5188
  Micoli F, Costantino P, Adamo R "Potential targets for next generation anti-microbial glycoconjugate vaccines" - FEMS Microbiology Reviews 42(3) (2018) 388-423
  

  Cell surface carbohydrates have been proven optimal targets for vaccine development. Conjugation of polysaccharides to a carrier protein triggers a T-cell dependent immune response to the glycan moiety. Licensed glycoconjugate vaccines are produced by chemical conjugation of capsular polysaccharides to prevent meningitis caused by meningococcus, pneumococcus and Haemophilus influenzae type b. However, other classes of carbohydrates (O-antigens, exopolysaccharides, wall/teichoic acids) represent attractive targets for developing vaccines.Recent analysis from WHO/CHO underpins alarming concern towards antibiotic resistant bacteria, such as the so called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) and additional pathogens such as Clostridium difficile and Group A Streptococcus. Fungal infections are also becoming increasingly invasive for immunocompromised patients or hospitalized individuals. Other emergencies could derive from bacteria which spread during environmental calamities (Vibrio cholerae) or with potential as bioterrorism weapons (Burkholderia pseudomallei and mallei, Francisella tularensis). Vaccination could aid reducing the use of broad spectrum antibiotics and provide protection by herd immunity also to individuals who are not vaccinated.This review analyses structural and functional differences of the polysaccharides exposed on the surface of emerging pathogenic bacteria, combined with medical need and technological feasibility of corresponding glycoconjugate vaccines.

  carbohydrates, glycoconjugates, vaccines, glycoengineering, antimicrobial resistance

  NCBI PubMed ID: 29547971
  Publication DOI: 10.1093/femsre/fuy011
  Journal NLM ID: 8902526
  Publisher: Oxford University Press
  Correspondence: Roberto Adamo
  Institutions: GSK Vaccines Institute for Global Health (GVGH), Via Fiorentina 1, 53100 Siena
  
   
  
  Neisseria meningitidis X
  CSDB ID 12710 (all data & tools)
• Article ID: 5189
  Ming SA, Cottman-Thomas E, Black NC, Chen Y, Veeramachineni V, Peterson DC, Chen X, Tedaldi LM, Wagner GK, Cai C, Linhardt RJ, Vann WF "Interaction of Neisseria meningitidis Group X N-acetylglucosamine-1-phosphotransferase with its donor substrate" - Glycobiology 28(2) (2018) 100-107
  

  Neisseria meningitidis Group X is an emerging cause of bacterial meningitis in Sub-Saharan Africa. The capsular polysaccharide of Group X is a homopolymer of N-acetylglucosamine α(1-4) phosphate and is a vaccine target for prevention of disease associated with this meningococcal serogroup. We have demonstrated previously that the formation of the polymer is catalyzed by a phosphotransferase which transfers N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to the 4-hydroxyl of the N-acetylglucosamine on the nonreducing end of the growing chain. In this study, we use substrate analogs of UDP-GlcNAc to define the enzyme/donor substrate interactions critical for catalysis. Our kinetic analysis of the phosphotransferase reaction is consistent with a sequential mechanism of substrate addition and product release. The use of novel uracil modified analogs designed by Wagner et al. enabled us to assess whether the CsxA-catalyzed reaction is consistent with a donor dependent conformational change. As expected with this model for glycosyltransferases, UDP-GlcNAc analogs with bulky uracil modifications are not substrates but are inhibitors. An analog with a smaller iodo uracil substitution is a substrate and a less potent inhibitor. Moreover, our survey of analogs with modifications on the N-acetylglucosamine residue of the sugar nucleotide donor highlights the importance of substituents at C2 and C4 of the sugar residue. The hydroxyl group at C4 and the structure of the acyl group at C2 are very important for specificity and substrate interactions during the polymerization reaction. While most analogs modified at C2 were inhibitors, acetamido analogs were also substrates suggesting the importance of the carbonyl group.

  capsular polysaccharide, GlcNAc phosphotransferase, UDP-GlcNAc analogs

  NCBI PubMed ID: 29228283
  Publication DOI: 10.1093/glycob/cwx100
  Journal NLM ID: 9104124
  Publisher: IRL Press at Oxford University Press
  Correspondence: willie.vann@fda.hhs.gov
  Institutions: Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA, Laboratory of Bacterial Polysaccharides, FDA, Silver Spring, MD 20993, USA, Department of Chemistry, University of California, Davis, CA 95616, USA, Department of Chemistry, King's College, London SE 11DB, UK
  Methods: kinetics assays, inhibition studies, biochemical methods, HPLC, enzymatic analysis
  
   
  
  Neisseria meningitidis X
  CSDB ID 12948 (all data & tools)
• Article ID: 5774
  Gomez-Redondo M, Arda A, Gimeno A, Jiménez-Barbero J "Bacterial polysaccharides: conformation, dynamics and molecular recognition by antibodies" - Drug Discovery Today: Technologies (2020) 1-11
  

  Bacterial infections are the cause of different severe health conditions and new therapies to combat these pathogens have been widely investigated. Carbohydrates, being complex structures covering the surface of bacteria, are considered relevant targets for antibody and vaccine development. The biological activities in pathogenesis of bacterial capsular polysaccharides and lipopolisaccharides and their unique structures have boosted the study of the minimal antigenic binding epitopes and the structural details of antibody-carbohydrate recognition. This review describes the most recent advances on the field, examining the structure, conformation and dynamics of relevant bacterial carbohydrates and their complexes with antibodies. The understanding of key factors governing the recognition process is fundamental for the progress toward the development of specific and efficient bacterial therapeutics.

  conformation, structure, capsular polysaccharides, epitope, recognition, dynamics, binding, vaccine, bacterial infection

  NCBI PubMed ID: 33388123
  Publication DOI: 10.1016/j.ddtec.2020.08.002
  Journal NLM ID: 101235076
  Publisher: Oxford: Elsevier
  Institutions: CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology Park, Building 800, 48160 Derio, Spain, Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain, Department Organic Chemistry II, Faculty of Science and technology, UPV-EHU, 48940 Leioa, Spain
  
   
  
  Neisseria meningitidis X
  CSDB ID 3673 (all data & tools)
• Article ID: 6024
  Adegbite A, McCarthy PC "Recent and Future Advances in the Chemoenzymatic Synthesis of Homogeneous Glycans for Bacterial Glycoconjugate Vaccine Development" - Vaccines 9(9) (2021) 1021
  

  Vaccines are important in preventing disease outbreaks and controlling the spread of disease in a population. A variety of vaccines exist, including subunit, recombinant, and conjugate vaccines. Glycoconjugate vaccines have been an important tool to fight against diseases caused by a number of bacteria. Glycoconjugate vaccines are often heterogeneous. Vaccines of the future are becoming more rationally designed to have a defined oligosaccharide chain length and position of conjugation. Homogenous vaccines could play an important role in assessing the relationship between vaccine structure and immune response. This review focuses on recent advances in the chemoenzymatic production of defined bacterial oligosaccharides for vaccine development with a focus on Neisseria meningitidis and selected WHO-prioritized antibacterial resistant-pathogens. We also provide some perspective on future advances in the chemoenzymatic synthesis of well-defined oligosaccharides.

  synthesis, glycoconjugate vaccines, chemoenzymatic synthesis, bacterial pathogens

  NCBI PubMed ID: 34579258
  Publication DOI: 10.3390/vaccines9091021
  Journal NLM ID: 101629355
  Publisher: Basel, Switzerland: MDPI AG
  Correspondence: Pumtiwitt.McCarthy@morgan.edu
  Institutions: Department of Chemistry, Morgan State University, Baltimore, MD, USA, Bioenvironmental Sciences Program, Morgan State University, Baltimore, MD, USA
  
   
  
  Neisseria meningitidis X
  CSDB ID 10815 (all data & tools)
• Article ID: 6096
  Kuttel MM, Berti F, Ravenscroft N "Molecular modeling provides insights into the loading of sialic acid-containing antigens onto CRM 197: the role of chain flexibility in conjugation efficiency and glycoconjugate architecture" - Glycoconjugate Journal 38(4) (2021) 411-419
  

  Vaccination is the most cost-effective way to control disease caused by encapsulated bacteria; the capsular polysaccharide (CPS) is the primary virulence factor and vaccine target. Neisseria meningitidis (Nm) serogroups B, C, Y and W all contain sialic acid, a common surface feature of human pathogens. Two protein-based vaccines against serogroup B infection are available for human use while four tetravalent conjugate vaccines including serogroups C, W and Y have been licensed. The tetravalent Menveo® conjugate vaccine is well-defined: a simple monomeric structure of oligosaccharides terminally conjugated to amino groups of the carrier protein CRM197. However, not only is there a surprisingly low limit for antigen chain attachment to CRM197, but different serogroup saccharides have consistently different CRM197 loading, the reasons for which are unclear. Understanding this phenomenon is important for the long-term goal of controlling conjugation to prepare conjugate vaccines of optimal immunogenicity. Here we use molecular modeling to explore whether antigen flexibility can explain the varying antigen loading of the conjugates. Because flexibility is difficult to separate from other structural factors, we focus on sialic-acid containing CPS present in current glycoconjugate vaccines: serogroups NmC, NmW and NmY. Our simulations reveal a correlation between Nm antigen flexibility (NmW > NmC > NmY) and the number of chains attached to CRM197, suggesting that increased flexibility enables accommodation of additional chains on the protein surface. Further, in silico models of the glycoconjugates confirm the relatively large hydrodynamic size of the saccharide chains and indicate steric constraints to further conjugation.

  Neisseria meningitidis, capsular polysaccharide, molecular modeling, Antigen conformation, conjugation efficiency, glycoconjugate structure

  NCBI PubMed ID: 33721150
  Publication DOI: 10.1007/s10719-021-09991-x
  Journal NLM ID: 8603310
  Publisher: Kluwer Academic Publishers
  Correspondence: neil.ravenscroft@uct.ac.za
  Institutions: Department of Computer Science, University of Cape Town, 7701, Cape Town, South Africa, Technical Research & Development, GSK Vaccines S.r.l, Via Fiorentina 1, 53100, Siena, Italy, Department of Chemistry, University of Cape Town, 7701, Cape Town, South Africa
  Methods: MD simulations, molecular modeling, CarbBuilder, CHARMM36
  
   
  
  Neisseria meningitidis X
  CSDB ID 9667 (all data & tools)
• Article ID: 6211
  Del Bino L, Osterlid KE, Wu DY, Nonne F, Romano MR, Codée J, Adamo R "Synthetic Glycans to Improve Current Glycoconjugate Vaccines and Fight Antimicrobial Resistance" - Chemical Reviews 122(20) (2022) 15672-15716
  

  Antimicrobial resistance (AMR) is emerging as the next potential pandemic. Different microorganisms, including the bacteria Acinetobacter baumannii, Clostridioides difficile, Escherichia coli, Enterococcus faecium, Klebsiella pneumoniae, Neisseria gonorrhoeae, Pseudomonas aeruginosa, non-typhoidal Salmonella, and Staphylococcus aureus, and the fungus Candida auris, have been identified by the WHO and CDC as urgent or serious AMR threats. Others, such as group A and B Streptococci, are classified as concerning threats. Glycoconjugate vaccines have been demonstrated to be an efficacious and cost-effective measure to combat infections against Haemophilus influenzae, Neisseria meningitis, Streptococcus pneumoniae, and, more recently, Salmonella typhi. Recent times have seen enormous progress in methodologies for the assembly of complex glycans and glycoconjugates, with developments in synthetic, chemoenzymatic, and glycoengineering methodologies. This review analyzes the advancement of glycoconjugate vaccines based on synthetic carbohydrates to improve existing vaccines and identify novel candidates to combat AMR. Through this literature survey we built an overview of structure-immunogenicity relationships from available data and identify gaps and areas for further research to better exploit the peculiar role of carbohydrates as vaccine targets and create the next generation of synthetic carbohydrate-based vaccines.

  carbohydrates, glycan, glycoconjugate vaccine

  NCBI PubMed ID: 35608633
  Publication DOI: 10.1021/acs.chemrev.2c00021
  Journal NLM ID: 2985134R
  Publisher: Chem Rev
  Correspondence: J. Codée ; R. Adamo
  Institutions: GSK, R&D, 53100 Siena, Italy, Leiden Institute of Chemistry, Leiden University, 2300 RA Leiden, The Netherlands
  
   
  
  Neisseria meningitidis X
  CSDB ID 20871 (all data & tools)
• Article ID: 6318
  Srtefanetti G, Maclennan CA, Micoli F "Impact and Control of Sugar Size in Glycoconjugate Vaccines" - Molecules 27(19) (2022) 6432
  

  Glycoconjugate vaccines have contributed enormously to reducing and controlling encapsulated bacterial infections for over thirty years. Glycoconjugate vaccines are based on a carbohydrate antigen that is covalently linked to a carrier protein; this is necessary to cause T cell responses for optimal immunogenicity, and to protect young children. Many interdependent parameters affect the immunogenicity of glycoconjugate vaccines, including the size of the saccharide antigen. Here, we examine and discuss the impact of glycan chain length on the efficacy of glycoconjugate vaccines and report the methods employed to size polysaccharide antigens, while highlighting the underlying reaction mechanisms. A better understanding of the impact of key parameters on the immunogenicity of glycoconjugates is critical to developing a new generation of highly effective vaccines.

  glycoconjugates, vaccine, immunogenicity, fragmentation of polysaccharides, sugar length

  NCBI PubMed ID: 36234967
  Publication DOI: 10.3390/molecules27196432
  Journal NLM ID: 100964009
  Publisher: Basel, Switzerland: MDPI
  Correspondence: G. Srtefanetti
  Institutions: Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy, Enteric and Diarrheal Diseases, Global Health, Bill & Melinda Gates Foundation, 500 5th Ave. N, Seattle, WA 98109, USA, The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK, The Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK, GSK Vaccines Institute for Global Health, 53100 Siena, Italy
  
   
  
  Neisseria meningitidis X
  CSDB ID 8816 (all data & tools)

Show legend Show as text

Structure type: polymer chemical repeating unit
Trivial name: teichoic acid
Compound class: cell wall polysaccharide
Contained glycoepitopes: IEDB_141807,IEDB_150077,IEDB_151531,IEDB_1711617

• Article ID: 4098
  Potekhina NV, Streshinskaia GM, Tul'skaya EM, Kozlova YI, Senchenkova SN, Shashkov AS "Phosphate-containing polymers of cell wall of bacilli" - Biochemistry (Moscow) 76(7) (2011) 745-754
  

  Anionic phosphate-containing cell wall polymers of bacilli are represented by teichoic acids and poly(glycosyl 1-phosphates). Different locations of phosphodiester bonds in the main chain of teichoic acids as well as the nature and combination of the constituent structural elements underlie their structural diversity. Currently, the structures of teichoic acids of bacilli can be classified into three types, viz. poly(polyol phosphates) with glycerol or ribitol as the polyol; poly(glycosylpolyol phosphates), mainly glycerol-containing polymers; and poly(acylglycosylglycerol phosphate), in which the components are covalently linked through glycosidic, phosphodiester, and amide bonds. In addition to teichoic acids, poly(glycosyl 1-phosphates) with mono- and disaccharide residues in the repeating units have been detected in cell walls of several Bacillus subtilis and Bacillus pumilus strains. The known structures of teichoic acids and poly(glycosyl 1-phosphates) of B. subtilis, B. atrophaeus, B. licheniformis, B. pumilus, B. stearothermophilus, B. coagulans, B. cereus as well as oligomers that link the polymers to peptidoglycan are surveyed. The reported data on the structures of phosphate-containing polymers of different strains of B. subtilis suggest heterogeneity of the species and may be of interest for the taxonomy of bacilli to allow differentiation of closely related organisms according to the 'structures and composition of cell wall polymers' criterion.

  cell wall, teichoic acids, Bacillus, poly(glycosyl 1-phosphates)

  NCBI PubMed ID: 21999535
  Journal NLM ID: 0376536
  Publisher: Nauka/Interperiodica
  Correspondence: potekchina@hotbox.ru
  Institutions: Lomonosov Moscow State University, Russia
  
   
  
  Bacillus pumilus AHU 1650
  CSDB ID 26941 (all data & tools)

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Structure type: polymer chemical repeating unit
Trivial name: poly(glycosyl phosphate), glycosyl 1-phosphate polymer (GPP)
Compound class: cell wall polysaccharide
Contained glycoepitopes: IEDB_135813,IEDB_137340,IEDB_141807,IEDB_150077,IEDB_151531,IEDB_1711617

• Article ID: 4397
  Streshinskaya GM, Shashkov AS, Kozlova YI, Tul'skaya EM, Kudryashova EB, Senchenkova SN, Ariskina EV, Evtushenko LI, Potekhina NV "Cell wall teichoic acids of Bacillus licheniformis VKM B-511T, Bacillus pumilus VKM B-508T, and other strains previously assigned to Bacillus pumilus" - Mikrobiologiia = Microbiology [Russian] 81(4) (2012) 425-434
  

  The teichoic acids (TAs) of type strains, viz. Bacillus licheniformis VKM B-511T and Bacillus pumilus VKM B-508T, as well as phylogenetically close bacteria VKM B-424, VKM B-1554, and VKM B-711 previously assigned to Bacillus pumilus on the basis of morphological, physiological, and biochemical properties, were investigated. Three polymers were found in the cell wall of each of the 5 strains under study. Strains VKM B-508T, VKM B-424, and VKM B-1554 contained polymers of the same core: unsubstituted 1,3-poly(glycerol phosphate) (TA I) and 1,3-poly(glycerol phosphate) with O-D-Ala and N-acetyl-a-D-glucosamine substituents (TA II and TA III', respectively). The cell walls of two remaining strains contained TA I, TA II, and a poly(glycosylpolyol phosphate) with the following structure of repeating units: -6)-a-D-GlcpNAc(1-1)-snGro-(3-P-(TA III'') in 'Bacillus pumilus' VKM B-711 (100% 16S rRNA gene similarity with the type strain of Bacillus safensis) and -6)-a-D-Galp-(1-2)-snGro-(3-P-(TA III''') in Bacillus licheniformis VKM B-511T. The simultaneous presence of three different TAs in the cell walls was confirmed by the NMR spectroscopic DOSY methods. The structure of the polymers and localization of O-D-Ala residues were investigated by the chemical and NMR spectroscopic methods.

  NMR spectroscopy, teichoic acid, Bacillus licheniformis, taxonomy, Bacillus pumilus

  Publication DOI: 10.1134/S0026261712030125
  Journal NLM ID: 0376652
  Publisher: Moskva: Izdatelstvo Nauka
  Correspondence: streshinskaya@mail.ru
  Institutions: Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia, All-Russian Collection of Microorganisms (VKM), Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences, Pushchino, Russia, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
  Methods: 13C NMR, 1H NMR, NMR-2D, 31P NMR, paper chromatography, composition analysis, genetic methods, paper electrophoresis
  
   
  
  Bacillus pumilus AHU 1650
  CSDB ID 28646 (all data & tools)
• Article ID: 4450
  Naumova IB, Shashkov AS "Anionic polymers in cell walls of Gram-positive bacteria" - Biochemistry (Moscow) 62(8) (1997) 809-840
  

  Information on the prevalence, compositions, and structures of anionic carbohydrate-containing polymers of cell walls of Gram-positive bacteria is summarized. The data suggest that these polymers are important for normal functioning of bacterial cells and require further studies. Structural data on teichoic acids found in the literature published over the last few years are discussed. This is a very diverse class of polymers whose structure-specific pathways of degradation were studied and NMR spectra were examined. Unique comprehensive tables of 13C-NMR spectroscopic data (mainly obtained by the authors) on these polymers are given in the Appendix. Other tables summarize data on teichuronic acids, sugar-phosphate polymers, acid polysaccharides, and structural variants of bonds between acid polysaccharides and peptidoglycans known from the literature. Functions of anionic polymers and their possible chemotaxonomic applications are discussed

  13C-NMR, NMR, structure, cell wall, composition, teichoic acid, teichuronic acid, Gram-positive, gram-positive bacteria, taxonomy

  NCBI PubMed ID: 9360295
  Journal NLM ID: 0376536
  Publisher: Nauka/Interperiodica
  Institutions: School of Biology, Lomonosov Moscow State University, Russia
  
   
  
  Bacillus pumilus AHU 1650
  CSDB ID 29113 (all data & tools)

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Structure type: homopolymer ; n= or >3
Compound class: CPS
Contained glycoepitopes: IEDB_141807,IEDB_150077,IEDB_151531,IEDB_1711617

• Article ID: 5818
  Na L, Li R, Chen X "Recent progress in synthesis of carbohydrates with sugar nucleotide-dependent glycosyltransferases" - Current Opinion in Chemical Biology 61 (2020) 81-95
  

  Sugar nucleotide-dependent glycosyltransferases (GTs) are key enzymes that catalyze the formation of glycosidic bonds in nature. They have been increasingly applied in the synthesis of complex carbohydrates and glycoconjugates with or without in situ generation of sugar nucleotides. Human GTs are becoming more accessible and new bacterial GTs have been identified and characterized. An increasing number of crystal structures elucidated for GTs from mammalian and bacterial sources facilitate structure-based design of mutants as improved catalysts for synthesis. Automated platforms have also been developed for chemoenzymatic synthesis of carbohydrates. Recent progress in applying sugar nucleotide-dependent GTs in enzymatic and chemoenzymatic synthesis of mammalian glycans and glycoconjugates, bacterial surface glycans, and glycosylated natural products from bacteria and plants are reviewed.

  carbohydrate, glycosyltransferase, enzymatic synthesis, sugar nucleotide, chemoenzymatic synthesis, biocatalyst

  NCBI PubMed ID: 33310623
  Publication DOI: 10.1016/j.cbpa.2020.10.007
  Journal NLM ID: 9811312
  Publisher: London: Elsevier
  Correspondence: Chen Xi
  Institutions: Department of Chemistry, University of California Davis, Davis, CA, US
  
   
  
  Neisseria meningitidis X
  CSDB ID 5174 (all data & tools)

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Structure type: homopolymer ; n=3
Aglycon: 3-aminopropyl
Trivial name: glycan epitope (glycotope)
Compound class: CPS, glycoconjugate
Contained glycoepitopes: IEDB_141807,IEDB_150077,IEDB_151531,IEDB_1711617

• Article ID: 6170
  Zaslona ME, Downey AM, Seeberger PH, Moscovitz O "Semi- and fully synthetic carbohydrate vaccines against pathogenic bacteria: recent developments" - Biochemical Society Transactions 49(5) (2021) 2411-2429
  

  The importance of vaccine-induced protection was repeatedly demonstrated over the last three decades and emphasized during the recent COVID-19 pandemic as the safest and most effective way of preventing infectious diseases. Vaccines have controlled, and in some cases, eradicated global viral and bacterial infections with high efficiency and at a relatively low cost. Carbohydrates form the capsular sugar coat that surrounds the outer surface of human pathogenic bacteria. Specific surface-exposed bacterial carbohydrates serve as potent vaccine targets that broadened our toolbox against bacterial infections. Since first approved for commercial use, antibacterial carbohydrate-based vaccines mostly rely on inherently complex and heterogenous naturally derived polysaccharides, challenging to obtain in a pure, safe, and cost-effective manner. The introduction of synthetic fragments identical with bacterial capsular polysaccharides provided well-defined and homogenous structures that resolved many challenges of purified polysaccharides. The success of semisynthetic glycoconjugate vaccines against bacterial infections, now in different phases of clinical trials, opened up new possibilities and encouraged further development towards fully synthetic antibacterial vaccine solutions. In this mini-review, we describe the recent achievements in semi- and fully synthetic carbohydrate vaccines against a range of human pathogenic bacteria, focusing on preclinical and clinical studies.

  carbohydrates, capsular polysaccharides, bacteria, vaccines, synthetic carbohydrate, antibacterial vaccines

  NCBI PubMed ID: 34495299
  Publication DOI: 10.1042/BST20210766
  Journal NLM ID: 7506897
  Correspondence: Oren Moscovitz
  Institutions: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
  
   
  
  Neisseria meningitidis X
  CSDB ID 10435 (all data & tools)