Chemical Synthesis and Antigenicity Evaluation of an Aminoglycoside Trisaccharide Repeating Unit of Pseudomonas aeruginosa Serotype O5 O-Antigen Containing a Rare Dimeric-Man p N3NA.

Autor: Tian G; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China.; Biomolecular Systems Department, Max Planck Institute of Colloids and Interfaces, Am Muehlenberg 1, Potsdam 14476, Germany., Hu J; Wuxi School of Medicine, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China., Qin C; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China., Li L; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China., Ning Y; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China., Zhu S; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China., Xie S; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China., Zou X; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China., Seeberger PH; Biomolecular Systems Department, Max Planck Institute of Colloids and Interfaces, Am Muehlenberg 1, Potsdam 14476, Germany., Yin J; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, P.R. China.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2024 Jul 10; Vol. 146 (27), pp. 18427-18439. Date of Electronic Publication: 2024 Jun 30.
DOI: 10.1021/jacs.4c03814
Abstrakt: Pseudomonas aeruginosa bacteria are becoming increasingly resistant against multiple antibiotics. Therefore, the development of vaccines to prevent infections with these bacteria is an urgent medical need. While the immunological activity of lipopolysaccharide O-antigens in P. aeruginosa is well-known, the specific protective epitopes remain unidentified. Herein, we present the first chemical synthesis of highly functionalized aminoglycoside trisaccharide 1 and its acetamido derivative 2 found in the P. aeruginosa serotype O5 O-antigen. The synthesis of the trisaccharide targets is based on balancing the reactivity of disaccharide acceptors and monosaccharide donors. Glycosylations were analyzed by quantifying the reactivity of the hydroxyl group of the disaccharide acceptor using the orbital-weighted Fukui function and dual descriptor. The stereoselective formation of 1,2- cis -α-fucosylamine linkages was achieved through a combination of remote acyl participation and reagent modulation. The simultaneous S N 2 substitution of azide groups at C2' and C2″ enabled the efficient synthesis of 1,2- cis -β-linkages for both 2,3-diamino-D-mannuronic acids. Through a strategic orthogonal modification, the five amino groups on target trisaccharide 1 were equipped with a rare acetamidino (Am) and four acetyl (Ac) groups. Glycan microarray analyses of sera from patients infected with P. aeruginosa indicated that trisaccharides 1 and 2 are key antigenic epitopes of the serotype O5 O-antigen. The acetamidino group is not an essential determinant of antibody binding. The β-D-Man p NAc3NAcA residue is a key motif for the antigenicity of serotype O5 O-antigen. These findings serve as a foundation for the development of glycoconjugate vaccines targeting P. aeruginosa serotype O5.
Databáze: MEDLINE
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