Recruiting the host's immune system to target Helicobacter pylori's surface glycans.
Recruiting the host's immune system to target Helicobacter pylori's surface glycans.
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DOI：
10.1002/cbic.201300006
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发表时间：
2013-04-15
期刊：
影响因子：
3.2
通讯作者：
Dube, Danielle H.
中科院分区：
文献类型：
--
作者：
Kaewsapsak, Pornchai;Esonu, Onyinyechi;Dube, Danielle H.
由于对现有抗生素耐药的细菌菌株的流行增加，迫切需要新的抗菌策略。细菌聚糖是新治疗的一个有吸引力的目标，因为它们经常与发病机制有关，并且含有人类中不存在的独特结构。我们着手开发一种基于胃病原体幽门螺杆菌（Hp）表面聚糖的新型靶向策略。在这项研究中，代谢标记的细菌聚糖与含叠氮化物的糖允许选择性交付的免疫刺激剂叠氮化物覆盖的Hp。我们建立了Hp的表面聚糖标记的处理与代谢底物全乙酰化N-叠氮基乙酰葡糖胺（Ac 4GlcNAz）。相比之下，用Ac 4GlcNAz处理的哺乳动物细胞在细胞外聚糖内没有表现出化学标记的掺入。我们进一步证明了叠氮化物和膦之间的施陶丁格连接在酸性条件下进行，只有很小的效率损失。然后，我们用与免疫刺激剂2，4-二硝基苯基（DNP）结合的膦靶向叠氮化物覆盖的Hp，DNP是一种能够指导宿主对这些细胞的免疫反应的化合物。最后，我们报告说，免疫效应细胞在体外催化选择性损伤DNP覆盖的Hp在抗DNP抗体的存在下。本文报道的技术代表了基于其聚糖靶向Hp的新策略。
Due to the increased prevalence of bacterial strains that are resistant to existing antibiotics, there is an urgent need for new antibacterial strategies. Bacterial glycans are an attractive target for new treatments, as they are frequently linked to pathogenesis and contain distinctive structures that are absent in humans. We set out to develop a novel targeting strategy based on surface glycans present on the gastric pathogen Helicobacter pylori (Hp). In this study, metabolic labeling of bacterial glycans with an azide-containing sugar allowed selective delivery of immune stimulants to azide-covered Hp. We established that Hp’s surface glycans are labeled by treatment with the metabolic substrate peracetylated N-azidoacetylglucosamine (Ac4GlcNAz). By contrast, mammalian cells treated with Ac4GlcNAz exhibit no incorporation of the chemical label within extracellular glycans. We further demonstrated that the Staudinger ligation between azides and phosphines proceeds under acidic conditions with only a small loss of efficiency. We then targeted azide-covered Hp with phosphines conjugated to the immune stimulant 2,4-dinitrophenyl (DNP), a compound capable of directing a host immune response against these cells. Finally, we report that immune effector cells catalyze selective damage in vitro to DNP-covered Hp in the presence of anti-DNP antibodies. The technology reported herein represents a novel strategy to target Hp based on its glycans.
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