病原菌响应的益生元寡糖囊泡治疗感染性肠炎的研究

Infectious enteritis is a common intestinal disease caused by pathogenic bacteria infection, seriously threatening the health of patients. As the preferred drug for the treatment of infectious enteritis, antibiotics will kill intestinal probiotics without selectivity, worsening the imbalance of intestinal flora. The present proposal based on prebiotic oligosaccharide will treat infectious enteritis caused by Salmonella or Proteus with high efficacy. In detail, we will synthesize an amphiphilic compound consisted of a hydrophilic oligosaccharide, a disulfide linkage and a hydrophobic alkyl chain, by which an oligosaccharide vesicle is self-assembled. The structure will be characterized by TEM、SEM and DLS, drug release behavior will be studied with hydrogen sulfide. The bactericidal activity of oligosaccharide vesicles loaded with antibiotic against pathogens and the proliferative effects of oligosaccharide (vesicle fragments) on bifidobacterium will be evaluated in vitro or in vivo. Taking advantage of the disulfide linkage, the oligosaccharide vesicle can be triggered to disassemble by hydrogen sulfide from enteric pathogens, and simultaneously release drug site-specifically, benefitting increasing local drug concentration. Meanwhile, the residual oligosaccharide as prebiotic can promote bifidobacterium proliferation in the large intestine, contributing to restore the balance of intestinal flora. As a multifunctional drug delivery with perfect synchronization of targeted release and rebalance of gut flora, this strategy provides a new way to treat infectious enteritis with antibiotics and reduces the generating rate of bacterial resistance.

感染性肠炎是临床上常见的肠道疾病，严重威胁着人类的健康。作为首选药物，抗生素不仅杀灭病原菌而且会影响有益菌群，从而引起肠道微生态失衡。本申请拟采用一种基于肠道益生元寡糖的抗感染策略，高效治疗沙门氏杆菌和变形杆菌等常见的产硫化氢病原菌引起的肠道感染：通过点击化学合成含二硫键的益生元寡糖两亲分子，该分子在水溶液中自组装包裹抗生素形成寡糖囊泡；采用扫描电镜和透射电镜等手段对上述囊泡进行结构表征，同时考察寡糖囊泡对外源性硫化氢的响应；通过体内、体外实验来考察寡糖囊泡对病原菌的选择性杀灭效果，以及释放的寡糖对益生菌的增殖能力。该策略中的寡糖囊泡依赖病原菌释放硫化氢导致二硫键断裂，从而使得抗生素能在病灶处定点释放，提高局部药物的有效浓度，同时产生的寡糖能促进下游肠道中益生菌的生长，本申请不仅为治疗感染性肠炎提供了一种全新的思路，而且对减少抗生素耐药菌的产生具有重要意义。

感染性肠炎是临床上常见的肠道疾病，严重威胁着人类的健康。作为首选药物，抗生素不仅杀灭病原菌而且会影响有益菌群，从而引起肠道微生态失衡。本本项目设计了一种硫化氢响应的益生元寡糖囊泡负载环丙沙星来治疗沙门氏菌引起的感染性肠炎。通过点击化学合成含二硫键的益生元寡糖两亲分子，该分子在水溶液中自组装包裹抗生素形成寡糖囊泡；研究了该囊泡在体外对硫化氢和沙门氏菌的响应。通过小鼠模型证明该囊泡能阻止抗生素快速进入血液，同时在肠道中响应沙门氏菌产生的硫化氢，定点释放抗生素，提高局部药物浓度，高效清除病原菌，并且囊泡产生的低聚木糖能作为益生元促进乳酸菌的增殖。此外，该囊泡还能减轻抗生素（新霉素）对正常小鼠肠道菌群的扰动，本项目的结果为使用抗生素治疗感染性肠炎提供了一种新的策略，有助于实现抗生素的精准利用。