以化學合成法合成鮑氏不動桿菌的莢膜五醣並作為免疫抗體評估

鮑氏不動桿菌 (Acinetobacter baumannii) 為好氧性革蘭氏陰性桿菌，是一種伺機性病原體，主要存在於醫院內，被分類為院內感染菌種。雖然它的致病力低，但仍會感染器官移植或免疫系統較差的患者，並誘發其他嚴重疾病 (如敗血症等)，甚至危及生命。近年來，由於鮑氏不動桿菌對於抗生素逐漸產生抗藥性，且迅速擴散，使它在全球醫療健保體系中已經成為一種危險的病菌。在預防病菌感染上，細菌的多醣共軛疫苗有一些成功的實例，例如在肺炎鏈球菌 (Streptococcus pneumonia) 和腦膜炎雙球菌 (Neisseria meningitides) 的預防上，都有不錯的成效。所以我們對鮑氏不動桿菌的莢膜研究及醣共軛疫苗的開發深感興趣。最近的文獻報導指出，鮑氏不動桿菌的致病因子包含莢膜多醣（capsular polysaccharide）；另外針對鮑氏不動桿菌ATCC17978菌株的莢膜進一步分析，發現莢膜主要是由五醣為一個單體，並重複單體而組成 (如下圖所示)。由化學結構的觀點來看，這樣的結構非常獨特。目前也沒有文獻探討如何利用化學合成方法去對此菌莢膜中的醣類做研究。在本論文中，我們設計了一個化學合成方法，可以合成天然物五醣，也從中得到更小片段、類似物、中間物。而我們主要著重於結構較特別的單醣A之化學合成。在A的醣構築體 (saccharide building block) 中，以葡萄糖胺作為骨架。而單醣A中主要的化學轉換有：(1) 將C3位置的水平鍵 (equatorial) 羥基轉換成乙醯胺基。(2) 專一性只在C4位置建構乙醯、C5位置建構羧酸官能基。而這個建構單醣A的合成策略，預期可以被延續應用於合成五醣及其他片段當中。希望在未來，這些合成化合物可以被進一步的應用於抗原表位 (antigenic epitope) 的探討及免疫抗體評估。

關鍵字

鮑氏不動桿菌；莢膜多醣；化學合成；醣基化；醣構築體

並列摘要

Acinetobacter baumannii are an aerobic gram-negative bacillus and an opportunistic bacterial pathogen primarily associated with hospital-acquired infections. It has low virulence but is capable of causing infection in organ transplants and people with compromised immune systems and it can cause serious and life-threatening infections. During recent years, it has become an increasing danger to the global healthcare system as a result of its rapid proliferation and increasing resistance to antibiotics and disinfectants. There are some successful cases of preventing of bacterial infection, like Streptococcus pneumonia and Neisseria meningitides. Recent reports show that the capsular polysaccharide is a virulence factors. Their analytic results show that one of structures of A. baumannii ATCC 17978 CPS is composed by the pentasaccharide as repeating unit (show as below). From the chemical structure point of view, it is not only unique, but also no synthetic method has been reported. In this work, we would like to design a general and flexible synthetic method to prepare this pentasaccharide and its analogues including new fragments or intermediates. Most importantly, we focused on the synthesis of structurally unique and external monosaccharide A, using glucosamine as a starting material. Besides, the key transformations for preparing the A ring are : (1) the hydroxy group was converted to the acetamido group at the equatorially C3 position, and (2) the acetyl group at the C4 position and the carboxylic acid group at the C5 position were established. Expectedly, this approach toward the preparation of the monosaccharide A might be applied to the synthesis of the pentasaccharide and its derivatives or fragments, which allows us for further biological evaluation and immune response study in the future.

並列關鍵字

Acinetobacter baumannii ； capsular polysaccharide ； chemical synthesis ； glycosylation ； saccharide building blocks

參考文獻

3. Scott, P.; Deye, G.; Srinivasan, A.; Murray, C.; Moran, K.; Hulten, E.; Fishbain, J.; Craft, D.; Riddell, S.; Lindler, L.; Mancuso, J.; Milstrey, E.; Bautista, C. T.; Patel, J.; Ewell, A.; Hamilton, T.; Gaddy, C.; Tenney, M.; Christopher, G.; Petersen, K.; Endy, T.; Petruccelli, B., An outbreak of multidrug-resistant Acinetobacter baumannii-calcoaceticus complex infection in the US military health care system associated with military operations in Iraq. Clin. Infect. Dis. 2007, 44, 1577–1584.

4. Camp, C.; Tatum, O. L., A Review of Acinetobacter baumannii as a Highly Successful Pathogen in Times of War. Lab. Med. 2010, 41, 649–657.

5. Peleg, A. Y.; Seifert, H.; Paterson, D. L., Acinetobacter baumannii: emergence of a successful pathogen. Clin. Microbiol. Rev. 2008, 21, 538–582.

6. Sandra I. ; Leigh G.; Dieter H.M., The Inanimate Environment of an Intensive Care Unit as a Potential Source of Nosocomial Bacteria : Evidence for Long Survival of Acinetobactoer calcoaceticus. Infect. Cont. Hosp. Ep. 1989, 10, 402–407.

7. Wendt, C.; Dietze, B.; Dietz, E.; Ruden, H., Survival of Acinetobacter baumannii on Dry Surfaces. J. Clin. Microbiol. 1997, 35, 1394–1397.

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以化學合成法合成鮑氏不動桿菌的莢膜五醣並作為免疫抗體評估

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