請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72066完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 王宗興(Tsung-Shing Wang) | |
| dc.contributor.author | Yu-Wei Chiu | en |
| dc.contributor.author | 邱昱瑋 | zh_TW |
| dc.date.accessioned | 2021-06-17T06:21:38Z | - |
| dc.date.available | 2018-08-21 | |
| dc.date.copyright | 2018-08-21 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-18 | |
| dc.identifier.citation | 1. Schoepp, N. G.; Schlappi, T. S.; Curtis, M. S.; Butkovich, S. S.; Miller, S.; Humphries, R. M.; Ismagilov, R. F., Rapid pathogen-specific phenotypic antibiotic susceptibility testing using digital LAMP quantification in clinical samples. Sci Transl Med 2017, 9 (410).
2. Braun, V.; Pramanik, A.; Gwinner, T.; Koberle, M.; Bohn, E., Sideromycins: tools and antibiotics. Biometals 2009, 22 (1), 3-13. 3. Enright, M. C.; Robinson, D. A.; Randle, G.; Feil, E. J.; Grundmann, H.; Spratt, B. G., The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci U S A 2002, 99 (11), 7687-7692. 4. McGuinness, W. A.; Malachowa, N.; DeLeo, F. R., Vancomycin Resistance in Staphylococcus aureus. Yale J Biol Med 2017, 90 (2), 269-281. 5. Miethke, M.; Marahiel, M. A., Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 2007, 71 (3), 413-451. 6. Andrews, N. C., Disorders of iron metabolism. N Engl J Med 1999, 341 (26), 1986-1995. 7. Weinberg, E. D.; Miklossy, J., Iron withholding: a defense against disease. J Alzheimers Dis 2008, 13 (4), 451-463. 8. Schaible, U. E.; Kaufmann, S. H., Iron and microbial infection. Nat Rev Microbiol 2004, 2 (12), 946-953. 9. Raymond, K. N.; Dertz, E. A.; Kim, S. S., Enterobactin: an archetype for microbial iron transport. Proc Natl Acad Sci U S A 2003, 100 (7), 3584-3588. 10. Cornelissen, C. N.; Biswas, G. D.; Tsai, J.; Paruchuri, D. K.; Thompson, S. A.; Sparling, P. F., Gonococcal Transferrin-Binding Protein-1 Is Required for Transferrin Utilization and Is Homologous to Tonb-Dependent Outer-Membrane Receptors. J. Bacteriol. 1992, 174 (18), 5788-5797. 11. Caza, M.; Kronstad, J. W., Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans. Front Cell Infect Microbiol 2013, 3, 80. 12. Biswas, G. D.; Sparling, P. F., Characterization of Lbpa, the Structural Gene for a Lactoferrin Receptor in Neisseria-Gonorrhoeae. Infect. Immun. 1995, 63 (8), 2958-2967. 13. Allen, C. E.; Schmitt, M. P., HtaA Is an Iron-Regulated Hemin Binding Protein Involved in the Utilization of Heme Iron in Corynebacterium diphtheriae. J. Bacteriol. 2009, 191 (8), 2638-2648. 14. Shirataki, C.; Shoji, O.; Terada, M.; Ozaki, S.; Sugimoto, H.; Shiro, Y.; Watanabe, Y., Inhibition of heme uptake in Pseudomonas aeruginosa by its hemophore (HasA(p)) bound to synthetic metal complexes. Angew Chem Int Ed Engl 2014, 53 (11), 2862-2866. 15. Chu, B. C.; Garcia-Herrero, A.; Johanson, T. H.; Krewulak, K. D.; Lau, C. K.; Peacock, R. S.; Slavinskaya, Z.; Vogel, H. J., Siderophore uptake in bacteria and the battle for iron with the host; a bird's eye view. Biometals 2010, 23 (4), 601-611. 16. Beasley, F. C.; Marolda, C. L.; Cheung, J.; Buac, S.; Heinrichs, D. E., Staphylococcus aureus transporters Hts, Sir, and Sst capture iron liberated from human transferrin by Staphyloferrin A, Staphyloferrin B, and catecholamine stress hormones, respectively, and contribute to virulence. Infect Immun 2011, 79 (6), 2345-2355. 17. Lamont, I. L.; Beare, P. A.; Ochsner, U.; Vasil, A. I.; Vasil, M. L., Siderophore-mediated signaling regulates virulence factor production in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 2002, 99 (10), 7072-7077. 18. Dale, S. E.; Doherty-Kirby, A.; Lajoie, G.; Heinrichs, D. E., Role of siderophore biosynthesis in virulence of Staphylococcus aureus: identification and characterization of genes involved in production of a siderophore. Infect Immun 2004, 72 (1), 29-37. 19. Hider, R. C.; Kong, X. L., Chemistry and biology of siderophores. Nat Prod Rep 2010, 27 (5), 637-657. 20. Boukhalfa, H.; Crumbliss, A. L., Chemical aspects of siderophore mediated iron transport. Biometals 2002, 15 (4), 325-339. 21. Holden, V. I.; Bachman, M. A., Diverging roles of bacterial siderophores during infection. Metallomics 2015, 7 (6), 986-995. 22. Destoumieux-Garzon, D.; Thomas, X.; Santamaria, M.; Goulard, C.; Barthelemy, M.; Boscher, B.; Bessin, Y.; Molle, G.; Pons, A. M.; Letellier, L.; Peduzzi, J.; Rebuffat, S., Microcin E492 antibacterial activity: evidence for a TonB-dependent inner membrane permeabilization on Escherichia coli. Mol Microbiol 2003, 49 (4), 1031-1041. 23. Liu, R.; Miller, P. A.; Vakulenko, S. B.; Stewart, N. K.; Boggess, W. C.; Miller, M. J., A Synthetic Dual Drug Sideromycin Induces Gram-Negative Bacteria To Commit Suicide with a Gram-Positive Antibiotic. J Med Chem 2018, 61 (9), 3845-3854. 24. Hammer, N. D.; Skaar, E. P., Molecular mechanisms of Staphylococcus aureus iron acquisition. Annu Rev Microbiol 2011, 65, 129-147. 25. Konetschny-Rapp, S.; Jung, G.; Meiwes, J.; Zahner, H., Staphyloferrin A: a structurally new siderophore from staphylococci. Eur J Biochem 1990, 191 (1), 65-74. 26. Meiwes, J.; Fiedler, H. P.; Haag, H.; Zahner, H.; Konetschny-Rapp, S.; Jung, G., Isolation and characterization of staphyloferrin A, a compound with siderophore activity from Staphylococcus hyicus DSM 20459. FEMS Microbiol Lett 1990, 55 (1-2), 201-205. 27. Madsen, J. L.; Johnstone, T. C.; Nolan, E. M., Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus. J Am Chem Soc 2015, 137 (28), 9117-9127. 28. Park, R. Y.; Sun, H. Y.; Choi, M. H.; Bai, Y. H.; Shin, S. H., Staphylococcus aureus siderophore-mediated iron-acquisition system plays a dominant and essential role in the utilization of transferrin-bound iron. J Microbiol 2005, 43 (2), 183-190. 29. Beasley, F. C.; Heinrichs, D. E., Siderophore-mediated iron acquisition in the staphylococci. J Inorg Biochem 2010, 104 (3), 282-288. 30. Drechsel, H.; Winkelmann, G., The configuration of the chiral carbon atoms in staphyloferrin A and analysis of the transport properties in Staphylococcus aureus. Biometals 2005, 18 (1), 75-81. 31. Cotton, J. L.; Tao, J.; Balibar, C. J., Identification and characterization of the Staphylococcus aureus gene cluster coding for staphyloferrin A. Biochemistry 2009, 48 (5), 1025-1035. 32. Cooper, J. D.; Hannauer, M.; Marolda, C. L.; Briere, L. A.; Heinrichs, D. E., Identification of a positively charged platform in Staphylococcus aureus HtsA that is essential for ferric staphyloferrin A transport. Biochemistry 2014, 53 (31), 5060-5069. 33. Grigg, J. C.; Cooper, J. D.; Cheung, J.; Heinrichs, D. E.; Murphy, M. E., The Staphylococcus aureus siderophore receptor HtsA undergoes localized conformational changes to enclose staphyloferrin A in an arginine-rich binding pocket. J Biol Chem 2010, 285 (15), 11162-11171. 34. Takeuchi, Y.; Nagao, Y.; Toma, K.; Yoshikawa, Y.; Akiyama, T.; Nishioka, H.; Abe, H.; Harayama, T.; Yamamoto, S., Synthesis and siderophore activity of vibrioferrin and one of its diastereomeric isomers. Chem Pharm Bull 1999, 47 (9), 1284-1287. 35. Bugdahn, N.; Oberthur, M., Syntheses and Iron Binding Affinities of the Bacillus anthracis Siderophore Petrobactin and Sidechain-Modified Analogues. Eur J Org Chem 2014, 2014 (2), 426-435. 36. Abergel, R. J.; Zawadzka, A. M.; Raymond, K. N., Petrobactin-mediated iron transport in pathogenic bacteria: coordination chemistry of an unusual 3,4-catecholate/citrate siderophore. J Am Chem Soc 2008, 130 (7), 2124-2125. 37. Harris, W. R.; Carrano, C. J.; Raymond, K. N., Coordination Chemistry of Microbial Iron Transport Compounds .16. Isolation, Characterization, and Formation-Constants of Ferric Aerobactin. J Am Chem Soc 1979, 101 (10), 2722-2727. 38. Hall, M. D.; Yasgar, A.; Peryea, T.; Braisted, J. C.; Jadhav, A.; Simeonov, A.; Coussens, N. P., Fluorescence polarization assays in high-throughput screening and drug discovery: a review. Methods Appl Fluoresc 2016, 4 (2), 022001. 39. Buchli, R.; VanGundy, R. S.; Hickman-Miller, H. D.; Giberson, C. F.; Bardet, W.; Hildebrand, W. H., Development and validation of a fluorescence polarization-based competitive peptide-binding assay for HLA-A*0201--a new tool for epitope discovery. Biochemistry 2005, 44 (37), 12491-507. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72066 | - |
| dc.description.abstract | 耐甲氧西林金黃色葡萄球菌（MRSA）是β-內酰胺抗性金黃色葡萄球菌菌株，它在世界範圍內傳播並導致30％的死亡率。在宿主體內，金黃色葡萄球菌分泌鐵載體Staphyloferrin A（簡稱SA）以獲得三價鐵離子，這對其生長至關重要。因此，SA可能可以被用來作為針對金黃色葡萄球菌有專一性的辨識單元，設計一個鐵載體-抗生素共軛化合物，使抗生素能藉由SA的辨識通道而進入細菌體內，這種策略稱為[特洛伊木馬]。而了解SA如何被金黃色葡萄球菌吸收，能夠使我們更好的設計出新的鐵載體-抗生素共軛化合物。
在這裡，我們合成了幾種SA類似物來研究結構和細菌攝取之間的關係。我們藉由操縱鳥氨酸的手性、骨架大小和羧基以及檸檬酸手性，來探究SA結構對其細菌攝取效率的影響。 從研究中，我們發現SA手性的改變對鐵螯合能力幾乎沒有影響。我們合成出的螢光素-SA共軛物能夠標記金黃色葡萄球菌，但我們也發現，如果是用L-鳥氨酸作為骨架的SA類似物，標記金黃色葡萄球菌的效率就會差很多，因此我們認為維持D-鳥氨酸的手性對於標記金黃色葡萄球菌是很重要的。若要設計鐵載體-抗生素共軛物，就必須維持鳥氨酸的手性。 | zh_TW |
| dc.description.abstract | Methicillin-Resistant Staphylococcus aureus (MRSA) is β-lactam resistant S. aureus strain which spreads worldwide and causes 30% fatality death. Inside host, secreting Staphyloferrin A (SA) by S. aureus to acquire Fe(III) is vital to its growth. Hence, SA might be utilized as a strain-specific warhead against S. aureus in Trojan-horse antibiotic. Understanding how SA is taken up by S. aureus enable us to design novel siderophore-antimicrobial conjugates.
Here, we synthesized several analogs of SA to investigate the relationship between structure and bacterial uptake. We investigate how SA structure affect its bacterial uptake efficiency through manipulating the chirality, backbone size, and carboxyl group of ornithine, as well as citric acid chirality. Analogs with diverse chiral centers have little impact on iron chelation ability. With fluorescent SA analogs, we found that the change in chirality in ornithine backbone significantly decreased bacterial targeting, suggesting maintaining this chirality is necessary in molecular design of siderophore-antimicrobial conjugates. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T06:21:38Z (GMT). No. of bitstreams: 1 ntu-107-R05223213-1.pdf: 11043483 bytes, checksum: 6fcc6c7dc87f7e6a33b5104067394bbe (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | Contents
摘要 I Abstract II List of Figures V List of Tables VIII Abbreviation IX Chapter 1 Introduction 1 1-1 Antibiotic Resistance Crisis 1 1-2 Iron function in vivo 3 1-2.1 Homeostasis in Human 3 1-2.2 Iron Acquisition of Bacteria 4 1-3 Siderophore 6 1-3.1. Classes of Siderohphore 6 1-3.2. Siderophore Conjugates 7 1-3.3. S. aureus Siderophore Production 7 1-4 Staphyloferrin A 8 1-4.1. Biosynthesis and Transport of Staphyloferrin A 8 1-4.2. Coordination Chemistry and Crystallography of SA 10 1-4.3. Siderophore Chiraliy Influence on bacterial uptake 12 Chapter 2 Results and Discussion 13 2-1 Retrosynthesis of Staphyloferrin A analogs 13 2-2 Synthetic Path Design of Staphyloferrin A analogs 14 2-3 Synthesis of (S)- and (R)- Dibenzyl citric acid 16 2-4 Synthesis of Staphyloferrin A (SA) analogs 19 2-5 Conjugation of fluorophore with SA analogs 22 2-6 SA Analogs in the following studies 24 2-7 Iron Chelation Power of SA analogs 26 2-8 Recognition of Staphyloferrin A by Receptor HtsA 32 2-8.1. SA Binding affinity with receptor (HtsA) in vitro 32 2-8.2. Targeting S. aureus with fluorescent SA analogs 35 2-9 Bacterial uptake of Staphyloferrin A by S. aureus 40 Chapter 3 Conclusions 46 Chapter 4 Material and Methods 47 4-1 Synthesis and Characterization of Compounds 47 4-1.1. General Materials and Methods 47 4-1.2. Synthesis of dibenzyl citric acid. 48 4-1.3. Synthesis of Staphyloferrin A analogs. 50 4-2 Determination of extinction coefficients 71 4-3 Determination of pFe(III) values 75 4-4 Procedures for analogs-receptor binding studies 77 4-4.1. General Materials and Methods 77 4-4.2. Expression of HtsA proteins 78 4-4.3. Purification of HtsA proteins 78 4-4.4. Fluorescence polarization assay for HtsA 79 4-4.5. Determination of dissociation constants (Kd) 80 4-5 Bacteria Labeling Experiments 81 4-5.1. General experimental methods in bacteria labeling experiments 81 4-5.2. Imaging & Flow Cytometry 81 4-5.3. Growth Recovery Assays 82 References 84 Appendix 91 | |
| dc.language.iso | en | |
| dc.subject | 金黃色葡萄球菌 | zh_TW |
| dc.subject | 鐵載體 | zh_TW |
| dc.subject | Staphyloferrin A | en |
| dc.subject | Staphylococcus aureus | en |
| dc.subject | siderophore | en |
| dc.title | 探討金黃色葡萄球菌鐵載體Staphyloferrin A結構對於螯合鐵能力與細菌攝取的關係 | zh_TW |
| dc.title | Synthesis of Staphyloferrin A analogs to study the
effect on iron chelation and bacterial uptake | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 戴桓青(Hwan-Ching Tai),徐丞志(Cheng-Chih Hsu) | |
| dc.subject.keyword | 金黃色葡萄球菌,鐵載體, | zh_TW |
| dc.subject.keyword | Staphylococcus aureus,Staphyloferrin A,siderophore, | en |
| dc.relation.page | 136 | |
| dc.identifier.doi | 10.6342/NTU201803975 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-18 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-107-1.pdf 未授權公開取用 | 10.78 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。