海洋放線菌被認為是海洋生物活性物質來源之潛在資源。先前已有許多海洋天然物研究者從鏈黴菌(Streptomyces)中分離獲得許多具有特殊活性及新穎結構的二次代謝物，並進一步以這些活性海洋天然物作為開發新型藥物的來源。在本研究中，我們從小琉球外海深海底泥中分離出兩株海洋細菌LQ-II和GT，這兩株菌皆具有抑制白色念珠菌(Candida albicans)的作用。藉由16S rRNA定序分別確認為Streptomyces albogriseolu LQ-II，和S. gougerotii GT。
在先前的研究文獻整理得知不同種生物體或多或少皆會產生相同的二次代謝物。這種現象常造成天然物的重複分離。為了避免自不同物種中重複的分離出已知的化合物，我們希望藉由液相層析串聯式質譜儀(LC-MS/MS)和分子網絡(molecular networking)分析開發新的研究策略，以更快的搜尋結構新穎具生物的活性化合物。到目前為止，我們從S. albogriseolus LQ-II的乙酸乙酯萃取物已經分離出12個化合物;包括六個二酮哌嗪類(L1~L6)、一個纈氨黴素(L7) 、一個homononactinic acid (L8)、一個固醇類(L9)、一個對苯二甲酸乙二酯類(L11)、一個色胺類衍生物(L10)、一個核苷類(L12)，從S. gougerotii GT的乙酸乙酯萃取分離出14個化合物，八個二酮派嗪類(G1~G8) 、一個芴酮類(G13) 、一個β氧色胺(G14)。其中有三個已知γ-丁內酯類化合物(G10~G12)跟一個新的γ-丁內酯類衍生物(G9)。此26個化合物的活性抗菌與細胞毒殺作用試驗正在進行中。

Marine actinobacteria was considered as potential sources of bioactive compounds. Many natural products research pioneers found lots of bioactive secondary metabolites with novel skeletons from Streptomyces spp., some of which have been developed as new drugs. In our researches on marine microbial natural products, we found two marine-derived bacterial strains LQ-II and GT, which were isolated from the deep-sea sediments in the offshore of Siao-liou-ciou. Both strains showed apparently inhibitory effect against Candida albicans. By the 16S rRNA sequence analysis, the strains LQ-II and GT were identified as S. albogriseolus and S. gougerotii, respectively
Literature surveys indicated that different organisms can produce more or less similar compounds. It will confuse scientists to make reduplicative works on the isolation of known compounds. To avoid the reduplicative isolation, we plan to develop a new research strategy by the modern analytic equipment, LC-MS/MS, and the state-of-art computation, molecular modeling, to target the isolation of new compounds. Till now, we isolated 12 compounds from the ethyl acetate extract of S. albogriseolus LQ-II, including six diketopiperazines (L1~L6), one valinomycin (L7), one homononactinic acid derivative (L8), one steroid (L9), one N-acetyl-β-oxotryptamine (L10), one terephthalate (L11), one nucleoside (L12) and 14 compounds from the ethyl acetate extract of S. gougerotii GT, including eight diketopiperazines (G1~G8) , one 9-fluorenone (G13), one β-oxo tryptamine derivative (G14), and four γ-butyrolactone (G9~G12). Among them, one γ-butyrolactone is new compound (G9). The bioactivities of these isolates are under investigation.

Content
審定書 i
謝誌 ii
摘要 iii
Abstract iv
Content viii
List of Figures xii
List of Tables xxii
List of Abbreviations and Symbols xxiv
CHAPTER ONE Introduction and Background 1
1-1. Antibiotics 1
1-1-1. Antibiotics Definition 1
1-1-2. Antibiotics Function 2
1-1-3. Antibiotics History 2
1-1-4. Antibiotics Types 3
1-2. Marine Bacteria 4
1-3. Streptomyces spp. 5
1-4. Candida albicans 8
1-5. Mass Spectral Molecular Networking 12
1-6. Objectives 13
CHAPTER TWO Experimental Procedure 14
2-1. Experiment Methods 14
2-2. Marine Bacterium 16
2-2-1. Collection and Purification 16
2-2-2. Literature Review about Streptomyces albogriseolus. 17
2-2-3. Literature Review about Streptomyces gougerotii. 21
2-2-4. The Crude Extract Curve and Bioactivity of Marine Bacteria 21
2-3. Extraction, Isolation and Purification 23
2-3-1. Streptomyces albogriseolus Strain LQ-II 23
2-3-2. Streptomyces gougerotii Strain GT 30
CHAPTER THREE Resulted and Discussion 36
3-1. Structural Elucidation of Isolates from Strain LQ-II 36
Cyclo (L-Pro-L-Leu) (L1) 36
Cyclo (4-trans-hydroxy-L-Pro-L-Leu) (L2) 41
Cyclo (4-trans-hydroxy-D-Pro-D-Leu) (L3) 48
Cyclo (D-Pro-L-Phe) (L4) 56
Cyclo (L-Pro-L-Phe) (L5) 61
Cyclo (4-trans-hydroxy-D-Pro-L-Phe) (L6) 70
Valinomycin (L7) 76
Homononactinic acid (L8) 86
7α-Acetoxy-3α,12α-dihydroxy-5β-cholanoic acid (also name cholic acid, 7-acetate) (L9) 94
N-Acetyl-β-oxotryptamine (L10) 103
Bis (2-ethylhexyl) terephthalate (L11) 109
Uracil (L12) 116
3-2. Structural Elucidation of Isolates from Strain GT 120
Cyclo (Gly-L-Pro) (G1) 120
Cyclo (Val-Leu) (G2) 126
Cyclo (6-hydroxy-Pro-D-Leu) (G3) 132
Cyclo (6-hydroxy-Pro-D-Leu) (G4) 138
Cyclo (Gly-L-Phe) (G5) 147
Cyclo (L-Phe-L-Ala) (G6) 153
Cyclo (4-trans-hydroxy-L-Pro-L-Phe) (G7) 160
Cyclo (Tyr-Phe) (G8) 167
(4S),(10R)-Dihydroxy-11-methyl-dodec-2-en-1,4-olide (G9) 174
(4S),10-Dihydroxy-10-methyl-undec-2-en-1,4-olide (G10) 184
(4S),10-Dihydroxy-10-methyl-dodec-2-en-1,4-olide (G11) 192
(4S)-Hydroxy-10-methyl-11-oxo-dodec-2-en-1,4-olide (G12) 200
9-Fluorenone (G13) 208
ortho-Acetamidobenzamide (G14) 214
3-3. Literature Review about Diketopiperazine 221
3-3-1. Comparion with the 13C and 1H-NMR data of Didetopiperazine with D- and/or L-forms 221
3-3-2. Comparison with the Specific Rotation of Didetopiperazine with D- and/or L-form 230
3-4. Mass Information of Secondary Metabolites from Streptomyces spp. 232
3-4-1. LC-MS/MS 232
3-4-2. Mass Spectral Molecular Networking 234
3-5. Bioactivity 235
3-5-1. Anti-microbial Activity 235
3-5-2. Anti-HCV and Anti-DENV Activities 236
CHAPTER FOUR Conclusion 239
CHAPTER FIVE Materials and Methods 241
5-1. Materials 241
5-1-1. Medium for Streptomyces spp. 241
5-1-2. Medium for Candida albicans 242
5-1-3. Medium for Lactobaillus jensenii 243
5-1-4. Other Media 243
5-2. General Experimental Procedures 244
5-3. Separation Flowchart of Marine Bacteria 246
5-4. Bioactivities 251
5-4-1. Paper Disc Agar Diffusion Assay Method 1 251
5-4-2. Paper Disc Agar Diffusion Assay Method 2 251
5-4-3. Punching-plate Assay Method 1 252
5-4-4. Punching-plate Assay Method 2 252
5-4-5. Lactate Assay 253
5-4-6. Minimum Inhibitory Concentration (MIC) Assay 253
5-4-7. Antivirus Assays 255
5-5. Chemical Examination 257
5-5-1. Modified Mosher’s Method 257
CHAPTER SIX References 258
CHAPTER SEVEN Physical, Chemical and Spectral Data 267

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