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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 朱忠瀚 | zh_TW |
| dc.contributor.advisor | John Chung-Han Chu | en |
| dc.contributor.author | 張育棋 | zh_TW |
| dc.contributor.author | Yu-Chi Chang | en |
| dc.date.accessioned | 2026-02-11T16:35:42Z | - |
| dc.date.available | 2026-02-12 | - |
| dc.date.copyright | 2026-02-11 | - |
| dc.date.issued | 2026 | - |
| dc.date.submitted | 2026-02-04 | - |
| dc.identifier.citation | (1) Ikuta, K. S.; Swetschinski, L. R.; Robles Aguilar, G.; Sharara, F.; Mestrovic, T.; Gray, A. P.; Davis Weaver, N.; Wool, E. E.; Han, C.; Gershberg Hayoon, A.; et al. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2022, 400 (10369), 2221-2248.
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An entirely fmoc solid phase approach to the synthesis of daptomycin analogs. Pept. Sci. 2019, 111 (1), e23094. (49) Taylor, S. D. Synthesis, mechanism of action, and SAR studies on the cyclic lipopeptide antibiotic daptomycin. Can. J. Chem. 2024, 102 (7), 414-424. (50) Chatzi, K. B. O.; Gatos, D.; Stavropoulos, G. 2-Chlorotrityl chloride resin. Int. J. Pept. Protein Res. 1991, 37 (6), 513-520. (51) Lundquist, J. T., IV; Pelletier, J. C. Improved Solid-Phase Peptide Synthesis Method Utilizing α-Azide-Protected Amino Acids. Org. Lett. 2001, 3 (5), 781-783. (52) Kates, S. A.; Solé, N. A.; Johnson, C. R.; Hudson, D.; Barany, G.; Albericio, F. A novel, convenient, three-dimensional orthogonal strategy for solid-phase synthesis of cyclic peptides. Tetrahedron Lett. 1993, 34 (10), 1549-1552. (53) Hachmann, J.; Lebl, M. Alternative to Piperidine in Fmoc Solid-Phase Synthesis. J. Comb. Chem. 2006, 8 (2), 149-149. (54) Ali, A. M.; Taylor, S. D. Efficient Solid-Phase Synthesis of Sulfotyrosine Peptides using a Sulfate Protecting-Group Strategy. Angew. Chem. Int. Ed. 2009, 48 (11), 2024-2026. (55) Chow, H. Y.; Chen, D.; Li, X. Improved total synthesis of the antibiotic A54145B. Org. Biomol. Chem. 2020, 18 (23), 4401-4405. (56) Kong, J.; Wu, Z.-X.; Wei, L.; Chen, Z.-S.; Yoganathan, S. Exploration of Antibiotic Activity of Aminoglycosides, in Particular Ribostamycin Alone and in Combination With Ethylenediaminetetraacetic Acid Against Pathogenic Bacteria. Front. Microbiol. 2020, 11, 1718. (57) Liang, C.; Behnam, M. A. M.; Sundermann, T. R.; Klein, C. D. Phenylglycine racemization in Fmoc-based solid-phase peptide synthesis: Stereochemical stability is achieved by choice of reaction conditions. Tetrahedron Lett. 2017, 58 (24), 2325-2329. (58) Diamandas, M.; Moreira, R.; Taylor, S. D. Solid-Phase Total Synthesis of Dehydrotryptophan-Bearing Cyclic Peptides Tunicyclin B, Sclerotide A, CDA3a, and CDA4a using a Protected β-Hydroxytryptophan Building Block. Org. Lett. 2021, 23 (8), 3048-3052. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/101590 | - |
| dc.description.abstract | 抗生素抗藥性對公共衛生構成的威脅日益嚴重。為應對這一挑戰，開發新型抗生素勢在必行。鈣離子依賴性抗生素(Calcium-dependent antibiotic, CDA)是一類非核糖體合成的環狀脂肽。因其獨特的作用機制，使它們在未來的抗生藥物開發上受期待。CDA 藉由與鈣離子結合引發構型變化，從而抑制革蘭氏陽性菌生長，其生物活性高度依賴鈣離子的存在。然而，在人體內環境中，鈣離子的濃度不足以活化大部分的CDA。
在我們先前的研究中，合成了Laspartomycin C (LspC) 的衍生物，其環外第1 個與在環內的第7個胺基酸皆被替換成絲胺酸(serine, Ser)。此衍生物可被苯硼酸(phenylboronic acid, PBA)活化，不再須要鈣離子，使其轉變為一種硼依賴性抗生素(boron-dependent antibiotic, BDA)。在本研究中，我們將相同的Ser取代策略延伸至其他CDA，以評估PBA 是否同樣能活化它們的抗菌潛力。 我們挑選了三種CDA: 達托黴素(Daptomycin, DAP)、弗留利黴素Friulimicin B (FruB) 與CDAx。它們在結構上皆與LspC存在特定差異。我們利用固相胜肽合成法合成了Ser取代的衍生物與其對應的原始序列胜肽衍生物作為對照組，並以最低抑菌濃度試驗來評估其抗菌活性。 研究結果顯示，CDAx的 Ser 取代衍生物可被 PBA 活化，進而抑制細菌的生長；相對地，修改後的 FruB與DAP衍生物則未表現出可偵測的活性。這些結果揭示了將 CDA 轉化為BDA的 Ser 替換策略不具有普遍適用性。這種差異化的反應表明，儘管所有 CDA 皆透過鈣離子依賴性活化，但它們在CDA家族中的機制細節和結構要求存在異質性。 | zh_TW |
| dc.description.abstract | The rise of antibiotic resistance poses a growing threat to public health. To respond to this challenge, new antimicrobial agents are needed. Calcium-dependent antibiotics (CDA) are a class of non-ribosomally synthesized cyclic lipopeptides. CDAs inhibit Gram-positive bacteria by undergoing a conformational change upon binding calcium ion(s) (Ca(II)). Due to their unique mechanism of action, CDAs have shown potential as candidates for future antibiotic development. However, a major limitation to their clinical application is that the Ca(II) concentration in the human physiological environment is often insufficient to fully activate most CDA members.
In our previous study, we synthesized a LspC analogue, in which the first exocyclic and the seventh amino acids in the macrocycle were replaced with serine (Ser). This engineered derivative, unlike its native counterpart, could be activated by phenylboronic acid (PBA) and no longer required Ca(II), effectively transforming it into a boron-dependent antibiotic (BDA). In this work, we applied the same Ser-substitution strategy to three other structurally diverse CDAs: daptomycin (DAP), friulimicin B (FruB), and CDAx. Peptides were synthesized using solid-phase peptide synthesis, and their antibacterial activity was evaluated through minimum inhibitory concentration assays. Our results showed that only the Ser-substituted CDAx analogue exhibited PBA-dependent activation, while the Ser-analogues of FruB and DAP were inactive. These findings suggest that the Ser-substitution strategy to create BDAs from CDAs is not a generalizable strategy. This differential response indicates that despite sharing Ca(II)-dependent activation, the mechanistic details and structural requirements across the CDA family are likely different. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2026-02-11T16:35:42Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2026-02-11T16:35:42Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
謝誌 II 摘要 III Abstract IV Table of Contents VI List of Figures VIII List of Schemes IX List of Tables X Abbreviation XI Chapter 1. Introduction 1 1.1 Antibiotic resistance challenge 1 1.2 Calcium-dependent antibiotics 2 1.3 Synthesis of CDAs 7 1.3.1 Solid-phase peptide synthesis 7 1.3.2 Total synthesis of daptomycin 9 1.4 Boron-dependent antibiotic 13 Chapter 2. Results and Discussions 18 2.1 Daptomycin 18 2.1.1 Molecular design of DAP analogue 18 2.1.2 Synthesis of DAP(S) 19 2.1.3 Bioactivity of DAP(S) 26 2.2 CDAx 28 2.2.1 Molecular Design of CDAx analogues 28 2.2.2 Synthesis of CDAx analogues 29 2.2.3 Bioactivity of CDAx 33 2.3 Friulimicin B 35 2.3.1 Molecular Design of FruB analogue 35 2.3.2 Synthesis of FruB analogues 36 2.3.3 Bioactivity of FruB 37 Chapter 3. Conclusion 39 Chapter 4. Experimental section 41 Appendix 62 References 84 | - |
| dc.language.iso | en | - |
| dc.subject | 鈣依賴型抗生素 | - |
| dc.subject | 硼依賴型抗生素 | - |
| dc.subject | 拉斯帕托黴素 | - |
| dc.subject | 弗留利黴素 | - |
| dc.subject | 達托黴素 | - |
| dc.subject | 苯硼酸 | - |
| dc.subject | calcium-dependent antibiotic | - |
| dc.subject | boron-dependent antibiotic | - |
| dc.subject | laspartomycin | - |
| dc.subject | friulimicin | - |
| dc.subject | daptomycin | - |
| dc.subject | CDAx | - |
| dc.subject | phenylboronic acid | - |
| dc.title | 由鈣依賴性抗生素衍生之硼依賴性抗生素 | zh_TW |
| dc.title | Boron-Dependent Antibiotics Derived from Calcium Dependent Antibiotics | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 114-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 游景晴;張晉源;李彥君 | zh_TW |
| dc.contributor.oralexamcommittee | Ching-Ching Yu;Chin-Yuan Chang;Yen-Chun Lee | en |
| dc.subject.keyword | 鈣依賴型抗生素,硼依賴型抗生素拉斯帕托黴素弗留利黴素達托黴素苯硼酸 | zh_TW |
| dc.subject.keyword | calcium-dependent antibiotic,boron-dependent antibioticlaspartomycinfriulimicindaptomycinCDAxphenylboronic acid | en |
| dc.relation.page | 93 | - |
| dc.identifier.doi | 10.6342/NTU202600580 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2026-02-06 | - |
| dc.contributor.author-college | 理學院 | - |
| dc.contributor.author-dept | 化學系 | - |
| dc.date.embargo-lift | 2026-02-12 | - |
| 顯示於系所單位： | 化學系 | |
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