Abstract：
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 SN2 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-ManpNAc3NAcA 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.
摘要：
铜绿假单胞菌对多种抗生素的耐药性日益增强。因此,开发预防这些细菌感染的疫苗是迫切需要的医疗需求。尽管脂多糖O-抗原在铜绿假单胞菌中的免疫活性是众所周知的,特定的保护性表位仍未被识别。在这里，我们介绍了在铜绿假单胞菌血清型O5O抗原中发现的高度功能化的氨基糖苷三糖1及其乙酰氨基衍生物2的第一个化学合成。三糖靶标的合成基于平衡二糖受体和单糖供体的反应性。通过使用轨道加权Fukui函数和双描述符定量二糖受体的羟基的反应性来分析糖基化。1,2-顺式-α-岩藻糖胺键的立体选择性形成是通过远程酰基参与和试剂调节的组合实现的。在C2\'和C2''处叠氮化物基团的同时SN2取代使两种2,3-二氨基-D-甘露糖醛酸的1,2-顺式-β-键有效合成。通过战略正交修改，目标三糖1上的五个氨基配备了稀有的乙酰氨基（Am）和四个乙酰基（Ac）基团。来自感染铜绿假单胞菌的患者的血清的聚糖微阵列分析表明,三糖1和2是血清型O5〇-抗原的关键抗原表位。乙酰胺基不是抗体结合的必要决定因素。β-D-ManpNAc3NAcA残基是血清型O5O-抗原抗原性的关键基序。这些发现为开发靶向铜绿假单胞菌血清型O5的糖缀合物疫苗奠定了基础。
