Citation: Peng Shen, Han Lin, Yikai Bao, Haofei Hong, Zhimeng Wu. Synthesis and immunological study of a glycosylated wall teichoic acid-based vaccine against Staphylococcus aureus[J]. Chinese Chemical Letters, ;2023, 34(4): 107679. doi: 10.1016/j.cclet.2022.07.022 shu

Synthesis and immunological study of a glycosylated wall teichoic acid-based vaccine against Staphylococcus aureus

Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China

zhimengw@hotmail.com

Received Date: 11 May 2022
Revised Date: 5 July 2022
Accepted Date: 12 July 2022
Available Online: 14 July 2022

Figures(6)

Staphylococcus aureus wall teichoic acids (WTAs) are attractive targets for antibacterial vaccine development. In this study, three core glycosylated WTA structure, including α-1,4-GlcNAc, β-1,4-GlcNAc and β-1,3-GlcNAc modified ribitol phosphates containing a linker are chemically synthesized and conjugated with tetanus toxin (TT) carrier protein as vaccine candidates. In vivo immunological studies demonstrate that the synthesized glycosylated WTAs display high immunogenicity and all conjugates provoke strong immune responses and elicit high levels of specific IgG antibodies against the GlcNAc-modified WTA. Furthermore, antibodies elicited by the vaccine candidates remain the capability to recognize S. aureus cells and display significant opsonophagocytic activity to clear S. aureus. This study demonstrates that the core structure of glycosylated WTAs are effective antigens for constructing anti-S. aureus vaccines to prevent and control S. aureus infections.
- WTAs,
- Staphylococcus aureus,
- GlcNAc modifications,
- Glycoconjugates,
- Antibacterial vaccine
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Figure 1. (A) Structure of S. aureus WTA; (B) designed core structures of GlcNAc modified WTAs 7-9 as antigens and their protein conjugates 1-6 (C).

Scheme 1. Synthesis of β-1,4-GlcNAc and α-1,4-GlcNAc-modified ribitol phosphates 7 and 8. (a) NaBH₄, MeOH, 50 ℃, 30 min, 95%; (b) TrtCl, DMAP, pyridine, 80 ℃, overnight, 79%; (c) TMSOTf, 4Å MS, DCM, −20 ℃, 2 h, 95%; (d) Zn, AcOH, Ac₂O, THF, 3 h, 85%; (e) TBAF, AcOH, THF, 40 ℃, overnight, 98% for 15, 93% for 19; (f) PivCl, pyridine, I₂, r.t., 3 h, 69% for 17 and 21; (g) MeONa, MeOH, H₂, Pd(OH)₂/C, H₂O, 75% for 7, 65% for 8; (h) TMSOTf, 4Å MS, DCM/Et₂O (2:1), −78 ℃, 2 h, 85%.

Scheme 2. Synthesis of β-1,3-GlcNAc modified ribitol phosphates 9. (a) TrtCl, DMAP, pyridine, BnBr, NaH, DMF, 65%; (b) HCl, MeCN, r.t., 1 h, 91%; (c) PdCl₂, MeOH, overnight, 91%; (d) TrtCl, DMAP, pyridine, 80 ℃, overnight, 72%; (e) TBDPSCl, imidazole, DCM, r.t., 1 h, 88%; (f) TMSOTf, 4Å MS, DCM, −20 ℃, 2 h, 95%; (g) Zn, AcOH, Ac₂O, THF, 3 h, 97%; (h) TBAF, AcOH, THF, 40 ℃, overnight, 93%; (i) PivCl, pyridine, I₂, r.t., 3 h, 78%; (j) MeONa, MeOH, H₂, Pd(OH)₂/C, H₂O, 70%.

Figure 2. Synthesis of conjugates 1-6. Reagents and conditions: (a) disuccinimidyl glutarate, DMF:PBS (4:1), 5 h, r.t.; (b) TT/HSA, PBS, r.t., 3 days.

Figure 3. (A) ELISA results of total IgG and IgM antibody titers in the groups (conjugates 1 and 2 vaccination group, n = 5; conjugate 3 vaccination group, n = 4); (B) Cross-reactivity of total IgG antibodies in the pooled day 28 antisera of conjugates 1-3 with glycosylated WTA haptens in the form of HSA conjugates 4-6 used as coating antigens. ELISA results of the day 28 antisera from individual mice immunized with conjugates 1 (C), 2 (D) or 3 (E). The titers of the corresponding oligosaccharide-specific IgG1, IgG2b, IgG2c, and IgG3 antibodies are displayed. Error bars represent SD of three parallel experiments. ^*P < 0.05; ^**P < 0.01; ^***P < 0.001.

Figure 4. (A) FACS assays of the binding between S. aureus ATCC 29213 treated with precursor and mouse sera. (B) Opsonophagocytic activities of antisera from each group were measured using the OPK assay. Error bars represent the SD of three parallel experiments. NS, not significantly different, ^**P < 0.01, ^***P < 0.001, ^****P < 0.0001.