Semisynthetic Glycoconjugate Vaccine Lead against Klebsiella pneumoniae Serotype O2afg Induces Functional Antibodies and Reduces the Burden of Acute Pneumonia

IF 15.6 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of the American Chemical Society Pub Date : 2024-12-12 DOI:10.1021/jacs.4c13972

Dacheng Shen, Bruna M. S. Seco, Luiz Gustavo Teixeira Alves, Ling Yao, Maria Bräutigam, Bastian Opitz, Martin Witzenrath, Bettina C. Fries, Peter H. Seeberger

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Abstract

Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) bacteria are a serious global health concern due to their drug-resistance to nearly all available antibiotics, fast spread, and high mortality rate. O2afg is a major CR-Kp serotype in the sequence type 258 group (KPST258) that is weakly immunogenic in humans. Here, we describe the creation and evaluation of semisynthetic O2afg glycoconjugate vaccine leads containing one and two repeating units of the polysaccharide epitope that covers the surface of the bacteria conjugated to the carrier protein CRM₁₉₇. The semisynthetic glycoconjugate containing two repeating units induced functional IgG antibodies in rabbits with opsonophagocytic killing activity and enhanced complement activation and complement-mediated killing of CR-Kp. Passive immunization reduced the burden of acute pneumonia in mice and may represent an alternative to antimicrobial therapy. The semisynthetic glycoconjugate vaccine lead against CR-Kp expressing O2afg antigen is awaiting preclinical development.

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抗肺炎克雷伯菌血清型O2afg半合成糖结合物疫苗铅诱导功能抗体并减轻急性肺炎负担

耐碳青霉烯肺炎克雷伯菌（CR-Kp）细菌对几乎所有可用抗生素具有耐药性，传播速度快，死亡率高，是一个严重的全球卫生问题。O2afg是258型序列组（KPST258）中主要的CR-Kp血清型，在人类中具有弱免疫原性。在这里，我们描述了半合成的O2afg糖结合疫苗引线的创建和评估，该引线含有覆盖与载体蛋白CRM197结合的细菌表面的多糖表位的一个和两个重复单元。含有两个重复单位的半合成糖缀合物诱导兔产生功能性IgG抗体，具有调节噬细胞杀伤活性，增强补体活化和补体介导的CR-Kp杀伤。被动免疫减轻了小鼠急性肺炎的负担，可能是抗菌治疗的一种替代方法。针对表达O2afg抗原的CR-Kp的半合成糖结合疫苗正在等待临床前开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of the American Chemical Society 化学-化学综合

CiteScore

24.40

自引率

6.00%

发文量

2398

审稿时长

1.6 months

期刊介绍： The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.