Clostridium difficile PSI polysaccharide: synthesis of pentasaccharide repeating block, conjugation to exotoxin B subunit, and detection of natural anti-PSI IgG antibodies in horse serum.
Abstract: Clostridium difficile is the most common cause of antimicrobial-associated diarrhea in humans and may cause death. Previously, we discovered that C. difficile expresses three polysaccharides, named PSI, PSII, and PSIII. It has now been established that PSII is a conserved antigen abundantly present on the cell-surface and biofilm of C. difficile. In contrast, the expression of PSI and PSIII appears to be stochastic processes. In this work, the total chemical synthesis of the PSI pentasaccharide repeating unit carrying a linker at the reducing end, α-l-Rhap-(1→3)-β-d-Glcp-(1→4)-[α-l-Rhap-(1→3)]-α-d-Glcp-(1→2)-α-d-Glcp-(1→O(CH2)5NH2, was achieved by a linear synthesis strategy from four monosaccharide building blocks. The synthesized PSI pentasaccharide was conjugated to a subunit of C. difficile exotoxin B yielding a potential dual C. difficile vaccine. More significantly, sera from healthy horses were shown to contain natural anti-PSI IgG antibodies that detected both the synthetic non-phosphorylated PSI repeat and the native PSI polysaccharide, with a slightly higher recognition of the native PSI polysaccharide.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication Date: 2013-03-30 PubMed ID: 23597587DOI: 10.1016/j.carres.2013.03.018Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research examined the Clostridium difficile (C. difficile) bacteria and its PSI polysaccharide, achieving a total chemical synthesis of the polysaccharide’s repeating unit and discovering that horse serum contains natural anti-PSI antibodies. The synthesized pentasaccharide was linked to a subunit of the bacteria’s exotoxin, potentially creating a dual vaccine for C. difficile.
About C. Difficile and Its Polysaccharides
- Clostridium difficile is a bacterium known to cause severe diarrhea in humans, notably after antimicrobial treatment. It can also lead to life-threatening complications.
- The bacterial organism expresses three different polysaccharides: PSI, PSII, and PSIII. These substances, which consist of long chains of sugar molecules, are involved in various cellular processes, including cell-wall structuring and biofilm formation.
- While PSII is found abundantly on the surface and biofilm of C. difficile, the expressions of PSI and PSIII polysaccharides seem to be random processes (stochastic).
Synthesis of PSI Pentasaccharide Repeating Unit
- The researchers successfully synthesized the repeating unit of the PSI polysaccharide. This complex structure, a pentasaccharide (five linked sugar molecules), was created using a linear synthesis strategy and four separate monosaccharide building blocks.
- The synthesized PSI pentasaccharide was developed with a linker attached to the reducing end. This linker aids in chemical reactions, allowing other molecules to be attached to the pentasaccharide.
Creation of Potential Dual C. Difficile Vaccine
- Fusing the synthesized PSI pentasaccharide with a subunit of the C. difficile exotoxin B, the researchers potentially created a dual vaccine against C. difficile. The new synthesize compound could stimulate the body’s immune system to provide protection against both the bacterium and its exotoxin.
Natural Anti-PSI Antibodies in Horse Serum
- Horse serum, the clear portion of blood obtained after coagulation, was found to contain natural antibodies against PSI. These anti-PSI antibodies were capable of recognizing and binding to both the synthetic non-phosphorylated PSI and the natural PSI polysaccharide.
- This suggests that horses may have a natural immunity against C. difficile or at least the PSI polysaccharide, which could provide valuable insights into future therapeutic or preventive approaches against the bacterium.
Cite This Article
APA
Jiao Y, Ma Z, Hodgins D, Pequegnat B, Bertolo L, Arroyo L, Monteiro MA.
(2013).
Clostridium difficile PSI polysaccharide: synthesis of pentasaccharide repeating block, conjugation to exotoxin B subunit, and detection of natural anti-PSI IgG antibodies in horse serum.
Carbohydr Res, 378, 15-25.
https://doi.org/10.1016/j.carres.2013.03.018 Publication
Researcher Affiliations
- Department of Chemistry, University of Guelph, Guelph, ON, Canada.
MeSH Terms
- Animals
- Carbohydrate Sequence
- Chemistry Techniques, Synthetic
- Clostridioides difficile / chemistry
- Cysteine Endopeptidases / metabolism
- Glycosylation
- Horses / blood
- Immunoglobulin G / blood
- Immunoglobulin G / immunology
- Molecular Sequence Data
- Oligosaccharides / chemical synthesis
- Oligosaccharides / chemistry
- Polysaccharides, Bacterial / chemical synthesis
- Polysaccharides, Bacterial / chemistry
- Polysaccharides, Bacterial / immunology
- Polysaccharides, Bacterial / metabolism
Citations
This article has been cited 10 times.- Rohokale R, Guo Z. Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines.. ACS Infect Dis 2023 Feb 10;9(2):178-212.
- Zhang Y, Hu Y, Liu S, He H, Sun R, Lu G, Xiao G. Total synthesis of Lentinus giganteus glycans with antitumor activities via stereoselective α-glycosylation and orthogonal one-pot glycosylation strategies.. Chem Sci 2022 Jul 6;13(26):7755-7764.
- Del Bino L, Østerlid KE, Wu DY, Nonne F, Romano MR, Codée J, Adamo R. Synthetic Glycans to Improve Current Glycoconjugate Vaccines and Fight Antimicrobial Resistance.. Chem Rev 2022 Oct 26;122(20):15672-15716.
- Broecker F, Wegner E, Seco BMS, Kaplonek P, Bräutigam M, Ensser A, Pfister F, Daniel C, Martin CE, Mattner J, Seeberger PH. Synthetic Oligosaccharide-Based Vaccines Protect Mice from Clostridioides difficile Infections.. ACS Chem Biol 2019 Dec 20;14(12):2720-2728.
- Pequegnat B, Monteiro MA. Carbohydrate Scaffolds for the Study of the Autism-associated Bacterium, Clostridium bolteae.. Curr Med Chem 2019;26(35):6341-6348.
- Kirk JA, Banerji O, Fagan RP. Characteristics of the Clostridium difficile cell envelope and its importance in therapeutics.. Microb Biotechnol 2017 Jan;10(1):76-90.
- Broecker F, Hanske J, Martin CE, Baek JY, Wahlbrink A, Wojcik F, Hartmann L, Rademacher C, Anish C, Seeberger PH. Multivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans.. Nat Commun 2016 Apr 19;7:11224.
- Mathur H, Rea MC, Cotter PD, Ross RP, Hill C. The potential for emerging therapeutic options for Clostridium difficile infection.. Gut Microbes 2014;5(6):696-710.
- Chen X, Lamont JT. Overview of Clostridium difficile infection: implications for China.. Gastroenterol Rep (Oxf) 2013 Nov;1(3):153-8.
- Leuzzi R, Adamo R, Scarselli M. Vaccines against Clostridium difficile.. Hum Vaccin Immunother 2014;10(6):1466-77.
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