臺灣博碩士論文加值系統

本研究之目的為篩選新型之抗真菌劑以及糖蛋白輸送抑制劑，論文分成三部分：1、放線菌菌種之篩選，2、新型抗真菌劑之篩選以及3、醣蛋白質細胞內輸送抑制物質篩選。
本研究自全國各地採集85 個土壤樣本，及自台北市動物園收集188 個動物糞便樣本利用乾熱法、濕熱法、鹼處理法、SDS-yeast extract 處理法及phenol 處理法等五種前處理，以及M3 、AY 、GA 、HV 及AI等五種選擇性分離培養基，自土壤及糞便樣本中分離得1847株放線菌菌株，用於抗真菌劑及糖蛋白輸送抑制劑之篩選。
抗真菌劑篩選方面，首先利用Candida albican為主要檢定菌，由所分離之1847株放線菌中分離得104株具生產抗真菌劑之菌株，再利用Pythium splendens、Rhizoctonia solani、Phytophthora capsici等三種國內重要之植物病原真菌做為檢定菌，自該104株菌株中、挑選48株進行抗真菌活性檢測。最後選擇編號84A22之菌株進行活性物質研究。該菌株經鑑定為Streptomyces alboviridis。經發酵培養後，自其培養液以管柱層析法及HPLC純化出其活性物質，命名為alboviridimycin。利用mass、NMR及FT-IR等分析對alboviridimycin進行結構鑑定，知其分子量為1100，其結構尚未解明，但已知為一種depsipeptide，其胺基酸組成為alanine、valine、serine及其他胺基酸衍生物。Alboviridimycin對格蘭氏陰性菌如Escherichia coli、Pseudomonas aeruginosa及Xanthomonas campestris等具抑菌活性，其MIC為0.04g/ml，對Candida albicans 、Cryptococcus neoformans及Saccharomyces cerevisiae之MIC約為0.16-2.5 g/ml，對絲狀真菌亦具有抑制活性、不過對Penicillium citrinum、Trichophyton mentagrophytes、Microsporum canis及Rhizoctonia solani則無活性。已知之depsipeptide中僅Aureobasidium pullulans所生產之aureobasidin A具抗真菌活性。Alboviridimycin和aureobasidin A之結構明顯不同，故而為一種新型之抗真菌depsipeptide。
醣蛋白質細胞內輸送抑制物質篩選方面，篩選系統為由Takatsuki所開發，利用NDV病毒感染BHK21細胞後，該病毒會合成HN及F糖蛋白送至宿主細胞膜。F糖蛋白具有引發宿主細胞融合之活性，而HN蛋白則會引發紅血球凝集現象，當添加微生物培養萃取液後，若含有抑制糖蛋白細胞內輸送阻害之物質，則HN與F糖蛋白無法送至細胞膜，因而上述二項活性受到影響。利用此種篩選方法預期可篩選到HN及F糖蛋白輸送可能相關的各個steps之阻害物質。利用此篩選方法、由糞生放線菌中篩選得七株具有生產抑制物質活性菌株。挑選其中一株具有最大抑制活性菌株48P1I2, 進行活性物質之純化。根據此菌株之菌絲及孢子的顯微特徵與生化特性，此菌株屬於Streptomyces gougerotii。利用各種分離法純化抑制物質。此純化之活性物質暫時命名為GPT48。GPT48之分子量為548，其結構尚未解明。利用免疫螢光染色法解析及西方墨點試驗解析，在抑制劑作用下病毒糖蛋白蓄積部位，以了解抑制物質之作用位置。目前已知GPT48之作用位置位於cis-Golgi至middle-Golgi 間，作用之部位與已知之醣蛋白輸送抑制劑有所不同。

The aims of this study are to screen the novel antifungal antibiotic and glycoprotein intracellular transport inhibitor. It divied into three parts: 1, the screening for the strains of Actinomycetes, 2, the screening for novel antifungal antibiotics, and 3, screening for the glycoprotein intracellular transport inhibitor.
In this study, we collected 85 soil samples from Taiwan island and 188 feces samples from Taipei City Zoo. After using 5 soil pretreatment including dry heat treatment, moisture heat treatment, SDS-yeast treatment and phenol treatment and 5 isolation mediums including M3, AY, GA, HV and AI, we isolated 1847 strains of actinmycetes from those soil and feces samples. Those actinomycetes were fed into our screening systems for searching antifungal antibiotics and the glycoprotein transport inhibitors.
We use antifungal susceptibility test of Candida albican as the frist screening system for antifungal antibiotics. These 1847 actinomycetes were screened and selected 104 strains for antifungal activity against Candida albican. Then, the plant pathogenic fungi, Pythium splendens、Rhizoctonia solani and Phytophthora capsici, were used ass the test organisms for antifungal activity screening. By antifungal susceptibility test, these 104 actinomycetes were screened for antifungal activity against plant pathogenic fungi. A strain, 84A22, identified as Streptomyces alboviridis, against Pythium splendens and Phytophthora capsici was selected to purify its antifungal compound. The pure compound was obtained from fermentation broth by extraction with ethyl acetate, silica gel column chromatographies, and HPLC. The molecular weight of this compound is 1100 by mass spectrometry. Its structure is determined by NMR spectrometry and named as alboviridimycin..
Using the screening system mentioned below we try to identify the unique and specific inhibitors for glycoprotein transport from Actinomycetes. This screening system was constructed by using baby hamster kidney cell (BHK-21 cell) and New Castle Disease Virus (NDV) for screening the glycoprotein''s inhibition and presentation produced by virus. Syntium form-ation and hemaglutination are the two phenomena caused by the glycoproteins produced by NDV after infection. The F protein and HN protein produced by virus are the causes of syntium formation and why hemaglutination take place. We use microscope to observe the syntium formation to determine the F protein''s transportation and use the hemaglutination test to assay the presentation of HN protein in the cytosal. We select the substance that can inhibit the syntium formation caused by the transportation of F proteins block but cannot stop the HN protein synthesis. We used this screening system to select inhibitors from Actinomycetes and selected several candidates for further identification and characterization. And now, we choose the strain 48P1I2 which was identified as Streptomyces gougerotii as the production strain. After purification process, we get the purified compound and try to estimate its structure. At the same time, we also study the molecular mechanism of the inhibition of the glycoprotein intracellular transport inhibitor
ABSTRACT 8
縮寫 9
第一章、緒論 9
第一節、放線菌(Actinomyces) 10
一、放線菌(Actinomycetes)簡介 10
二、放線菌與生理活性物質之篩選 11
三、放線菌之工業用途 13
第二節、抗真菌劑 13
一、抗真菌劑簡介 13
二、抗真菌劑之作用機制 14
1、 作用在固醇類（sterol）生合成及功能上的抗真菌劑 14
2、作用在細胞核功能上的抗真菌劑 15
3、抑制真菌細胞壁生合成的抗真菌劑 15
4、作用在能量代謝的抗真菌劑 15
三、醫藥用抗真菌劑 15
1、 Polyenes系列抗真菌劑 16
2、Azoles系列抗真菌劑 16
3、Glucan 合成抑制劑 16
4、Chitin 合成抑制劑 16
5、Nucleoside 類似物 17
四、農業用抗真菌劑(William, 1986) 18
五、peptide類抗真菌劑(Robert and Daniel, 1999) 18
第三節、醣蛋白質細胞內輸送阻害物質 19
一、醣蛋白質細胞內輸送途徑 19
二、醣蛋白質細胞內輸送程序之解明 20
1、利用Saccharomyces cerevesia 蛋白輸送分泌變異株之研究法 20
2、利用動物細胞醣蛋白分泌阻害變異株之研究法[Tufaro, 1987 #172] 20
3、醣蛋白質細胞內輸送機制之in vitro 研究法 21
4、應用選擇性醣蛋白質細胞內輸送阻害劑之研究法 21
三、醣蛋白質細胞內輸送阻害劑及其應用(Takatsuki and Tamura, 1985) 21
四、醣蛋白質細胞內輸送阻害劑之應用 23
第四節、研究策略 24
第二章、材料與方法 26
第一節、材料 26
一、培養基及培養液 26
1、放線菌篩選培養基(Orchard and Goodfellow, 1974; Wakasman, 1961) 26
2、抗真菌劑篩選培養基 27
3、放線菌鑑定用培養基 29
4、醣蛋白胞內輸送抑制物發酵培養基 30
5、動物細胞培養基 31
二、菌種、細胞株、病毒及抗體： 31
1、抗菌活性檢定用 31
2、醣蛋白胞內輸送抑制物檢定 32
三、試藥及耗材： 33
1、化學藥品： 33
2、培養基及佐劑： 33
3、有機溶劑： 33
4、Paper disc： 33
四、層析管柱： 33
第二節、方法 35
一、篩選種源庫之建立 35
1、菌種分離 35
2、菌種培養與物質萃取 36
二、放線菌菌種鑑定 37
1、形態觀察： 37
2、細胞壁組成分析： 37
三、抗真菌劑之篩選與純化 38
1、對峙培養法： 38
2、paper disc agar diffusion assay： 38
3、醱酵培養 39
4、活性物質之萃取與純化 40
5、結構鑑定： 42
6、感受性測試： 43
7、細胞毒性測試(Tada et al., 1986; Veronique et al., 1992)： 44
四、醣蛋白質細胞內輸送抑制物質之篩選 45
1、抑制物質之篩選方法(Muroi et al., 1996; Seog et al., 1994) 45
2、醱酵培養 46
3、醣蛋白胞內輸送抑制物質純化 46
4、醣蛋白胞內輸送抑制物質鑑定 49
5、醣蛋白胞內輸送抑制物質機構 49
第三章、結果 52
第一節、放線菌菌株篩選 52
一、菌種分離 52
1、樣本採集： 52
2、樣本前處理(Steele, 1991)︰ 53
3、菌株分離培養基： 54
二、糞便樣本之放線菌菌株分離統計： 54
三、放線菌菌屬鑑定 55
1、形態觀察： 56
2、細胞壁組成分析： 56
第二節、活性物質之篩選 57
一、第一次對峙培養篩選 57
二、活性菌種鑑定 59
三、以植物病源菌為檢定菌之二次篩選 59
1、對峙培養法： 60
2、paper disc agar diffusion assay(Tamura et al., 1968)： 61
3、菌種鑑定： 61
第三節、Streptomyces alboviridis 84A22之抗真菌物質 62
一、醱酵培養： 62
二、84A22抗真菌物質之萃取與純化 63
1、第一次Silica gel 管柱層析： 63
2、第二次Silica gel 管柱層析： 63
3、製備級silica gel HPLC： 63
4、 分析級silica gel HPLC： 63
5、C18 HPLC： 64
6、phenyl HPLC： 64
三、結構鑑定 64
1、UV spectrum 64
2、mass spectrum 64
3、1H NMR spectrum 64
4、13C NMR spectrum 64
5、2D-NMR 65
6、FT-IR spectrum 65
7、amino acid composition 65
四、抗真菌劑抗菌性測試 66
1、細菌對alboviridimycin之感受性測試 66
2、酵母菌對alboviridimycin之感受性測試 66
3、alboviridimycin對黴菌之感受性測試 66
4、alboviridimycin對細胞之細胞毒性測試 67
第四節、醣蛋白細胞內輸送抑制物質之篩選 67
一、醣蛋白細胞內輸送抑制物質之篩選 67
二、48P1I2之菌種鑑定 68
1、細胞壁成分分析 68
2、形態特徵 68
3、醣類的利用及生理特性測試 68
4、菌絲與孢子之電子顯微鏡觀察 68
三、醣蛋白質細胞內輸送抑制物質GPT48之發酵培養 69
四、GPT48之萃取與純化： 69
1、Silica gel 管柱層析 I 69
2、Silica gel Silica gel 管柱層析 II 70
3、製備級silica gel HPLC： 70
4、分析級silica gel HPLC： 70
5、C18 HPLC： 70
6、phenyl HPLC： 70
五、醣蛋白胞內輸送抑制物質GPT48結構鑑定 71
1、mass spectrum 71
2、1H NMR spectrum 71
六、醣蛋白胞內輸送抑制劑GPT48抑制機制 71
1、GPT48處理後VSV-G 蛋白於細胞內蓄積部位之分析： 71
第四章、討論 74
第一節、放線菌菌種分離 74
第二節、抗真菌物質之篩選 76
一、抗真菌劑生產菌株之篩選 76
1、篩選方法 76
2、形態異常誘發 77
二、Streptomyces alboviridis之抗真菌劑alboviridimycin 78
1、Alboviridimycin之純化與結構鑑定 78
2、alboviridimycin之抗菌特性 79
3、alboviridimycin對細胞之細胞毒性測試 80
4、後續之研究 80
第三節、醣蛋白胞內輸送抑制物質之篩選 81
一、醣蛋白胞內輸送抑制物質之篩選 81
二、Streptomyces gougerotii之醣蛋白胞內輸送抑制物質GPT48 82
1、GPT48之純化與結構鑑定 82
2、GPT48之特性 83
3、後續之研究 86
第五章、參考文獻 87
第六章、附錄 100

封面
目錄
誌謝
中文摘要
ABSTRACT
縮寫表
第一章.緒論
第一節.放線菌(Actinomyces)
一.放線菌(Actinomyces)簡介
二.放線菌與生理活性物質之篩選
三.放線菌之工業用途
第二節.抗真菌劑
一.抗真菌劑簡介
二.抗真菌劑之作用機制
三.醫藥用抗真菌劑
四.農業用抗真菌劑(William,1986)
五.Peptide類抗真菌劑(Robert and Daniel,1999)
第三節.醣蛋白質細胞內輸送阻害物質
一.醣蛋白質細胞內輸送途徑
二.醣蛋白質細胞內輸送程序之解明
三.醣蛋白質細胞內輸送阻害劑及其應用(Takatsuki and Tamura,1985)
四.醣蛋白質細胞內輸送阻害劑之應用
第四節.研究策略
第二章.材料與方法
第一節.材料
一.培養基及培養液
二.菌種、細胞株、病毒及抗體:
三.試藥及耗材:
四.層析管柱:
第二節.方法
一.篩選種源庫之建立
二.放線菌菌種鑑定
三.抗真菌劑之篩選與純化
四.醣蛋白質細胞內輸送抑制物質之篩選
第三章.結果
第一節.放線菌菌株篩選
一.菌種分離
二.糞便樣本之放線菌菌株分離統計
三.放線菌菌屬鑑定
第二節.活性物質之篩選
一.第一次對峙培養篩選
二.活性菌種鑑定
三.以植物病源菌為檢定菌之二次篩選
第三節.Streptomyces alboviridis 84A22之抗真菌物質
一.醱酵培養:
二.84A22抗真菌物質之萃取與純化
三.結構鑑定
四.抗真菌劑抗菌性測試
第四節.醣蛋白細胞內輸送抑制物質之篩選
一.醣蛋白細胞內輸送抑制物質之篩選
二.48p1I2之菌種鑑定
三.醣蛋白質細胞內輸送抑制物質GPT48之發酵培養
四.GPT48之萃取與純化:
五.醣蛋白胞內輸送抑制物質GPT48結構鑑定
六.醣蛋白胞內輸送抑制劑GPT48抑制機制
第四章 討論
第一節.放線菌菌種分離
第二節.抗真菌物質之篩選
一.抗真菌劑生產菌之篩選
二.Streptomyces alboviridis之抗真菌劑 alboviridimycin
第三節.醣蛋白胞內輸送抑制物質之篩選
一.醣蛋白胞內輸送抑制物質之篩選
二.Streptomyces gougerotii之醣蛋白胞內輸送抑制物質GPT48
第五章.參考文獻
第六章.附錄

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