臺灣博碩士論文加值系統

對人體和病原菌而言，鐵元素是種極為重要的營養素。細菌體會分泌一些小分子的鐵螯合劑—鐵載體，用以從宿主體內獲取鐵元素。為在營養限制的環境下生存，金黃色葡萄球菌會產生多種鐵載體，如: staphyloferrin A。天然物staphyloferrin A 由(D)—鳥胺酸和兩個分別帶有(S)、(R)立體組態的檸檬酸所組成，本篇論文我們將之標記成DSR。目前對於帶有不同立體組態的staphyloferrin A是否會改變其螯合鐵的能力，抑或影響其結合受體，仍未充分地被研究。此篇碩士論文中，我們藉由有機合成的方式，合成一系列帶有特定立體組態的staphyloferrin A衍生物。為了測定各衍生物的螯合鐵能力，我們利用其他螯合物，如EDTA或EGTA來做滴定實驗。接著將螢光素綴合至衍生物上，可選擇性的標記金黃色葡萄球菌。此外利用fluorescence polarization 偵測衍生物與受體結合的強弱。實驗結果證實staphyloferrin A支鏈上檸檬酸的立體組態確實會改變其螯合鐵的能力，進而影響到與受體蛋白HtsA的結合。我們在此篇論文中發展了可控制立體組態的staphyloferrin A 合成方法以利後續鐵載體衍生物的研究。

Iron is a crucial nutrient for both humans and bacterial pathogens. Microorganisms produce high affinity chelating molecules called siderophores to acquire iron. Staphylococcus aureus elaborates different siderophores, such as staphyloferrin A (SA), to grow under iron-restricted condition. Native SA is composed of D-ornithine and two chiral citrates with R and S configurations, labeled as DSR. It is still unclear how stereo configurations in SA affects the iron chelation or receptor recognition. In this work, we chemically synthesized five SA analogues with different stereo configurations of ornithine and citrates (DSR, LSR, DRS, DSS, and DRR). Utilizing EDTA and EGTA as chelation competitors, we determined pFe(Ⅲ) values of SA stereoisomers by UV-visible spectrophotometry. Moreover, functionalized SA analogues were conjugated to fluorescein, thereby affording SA-(PEG)3-FL, it could selectively label S. aureus. Subsequently, we analyzed the binding affinity between SA stereoisomers and cognate receptor HtsA via fluorescence polarization. Our results suggested stereo figuration of side chain in staphyloferrin A influence the stability of siderophore-Fe(Ⅲ) complex, and then affect the recognition to HtsA. In conclusion, we have provide a synthetic strategy to manipulate stereo configurations in SA that would facilitate the application of siderophore conjugates.

摘要 I
Abstract II
Table of Contents III
List of Figures VII
List of Tables X
Abbreviations XI
Chapter 1 Introduction 1
1-1 Antibiotics in crisis 1
1-2 Transition Metal in Infectious Disease 4
1-3 Iron Homeostasis in Host-pathogen interaction 4
1-3.1. Importance of Iron Homeostasis in Bacteria 4
1-3.2. Iron Acquisition of Bacteria 7
1-4 Siderophore 9
1-4.1. Chemistry of Siderophores 9
1-4.2. Siderophore Conjugates 11
1-4.3. Biosynthesis and Synthesis of Staphyloferrin A 12
1-4.4. Biochemistry of Staphyloferrin A 13
1-4.5. Coordination Chemistry of Staphyloferrin A 15
1-4.6. Determination of iron chelation 18
Chapter 2 Results and Discussion 21
2-1 Retrosynthesis of staphyloferrin A analogues 21
2-2 Design of Staphyloferrin A analogues 22
2-3 Synthesis of (S)- and (R)- dibenzyl citric acid 23
Chiral resolution 24
2-4 Synthesis of SA Analogues 26
2-5 Conjugation of Functionalized SA Analogues 32
2-6 Fe(Ⅲ)-binding Properties of SA Stereoisomers 33
2-7 Determination of the Fe(Ⅲ)-Binding Affinities of SA Stereoisomers 36
2-8 Studies of Cognate Receptor HtsA-binding 40
2-9 Bacterial Labeling Experiments 43
Conclusion 48
Perspective 49
Chapter 3 Material and Methods 51
3-1 Synthesis and Characterization of Compounds 51
3-1.1. General Materials and Methods 51
3-1.2. Synthesis of dibenzyl citric acid 52
3-1.3. Synthesis of Staphyloferrin A analogues 55
3-1.4. Click reaction Fluorescein onto Staphyloferrin A analogues 67
3-1.5. Synthesis of o,o-EDDHA 69
3-2 Procedures for Fe(Ⅲ)-binding Studies 70
3-2.1. General Materials and Methods 70
3-2.2. Optical Absorption Spectroscopy 71
3-2.3. Circular Dichroism (CD) Spectorscopy 71
3-2.4. Determination of Extinction Coefficients 72
3-2.5. Determination of pFe(Ⅲ) 75
3-3 Procedures for cognate receptor-binding Studies 76
3-3.1. General Materials and Methods 76
3-3.2. Fluorescence polarization assay for HstA 77
3-3.3. Determination of dissociation constants (Kd) 77
3-4 Bacterial experiments 78
3-4.1. General experimental methods in bacterial experiments 78
3-4.2. Bacteria imaging experiments 79
3-4.3. Bacteria labeling experiments 80
References 81
Appendix Ⅰ 95
Appendix Ⅱ 128
Appendix Ⅲ 132
Appendix Ⅳ 139

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