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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳佩燁(Rita Pei-Yeh Chen) | |
| dc.contributor.author | Sung-Pang Chen | en |
| dc.contributor.author | 陳頌邦 | zh_TW |
| dc.date.accessioned | 2021-05-20T00:48:49Z | - |
| dc.date.available | 2025-12-01 | |
| dc.date.available | 2021-05-20T00:48:49Z | - |
| dc.date.copyright | 2020-12-04 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-11-26 | |
| dc.identifier.citation | [1] Haney EF, Hancock REW (2013). Peptide design for antimicrobial and immunomodulatory applications. Biopolymers. 100:572-583.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8085 | - |
| dc.description.abstract | 近年來，由於抗生素藥物的過度使用造成抗藥性菌株的大量出現，且新的抗生素發展速度緩慢，發展新型態的抗生素已成為當務之急。抗微生物胜肽(Antimicrobial peptides，AMPs) 或稱為抗菌胜肽，被認為極具潛力發展成為取代傳統抗生素的新一類抗生素。 在實驗室先前的研究中，我們設計了五條陽離子抗菌胜肽，均由18個胺基酸組成，擁有不同的疏水性/親水性胺基酸分佈。在經過初步的抗菌活性測試(Minimal Inhibitory Concentration/ Minimal Bactericidal Concentration ; MIC/MBC測試) 後，我們挑選了抗菌活性最好的胜肽，並在本研究中，以此胜肽為模板進行不同的修飾，例如縮短胜肽長度、替換相同性質的胺基酸、改變N端的保護基、使用D-form胺基酸或在序列中加入類肽結構。我們測試這些修飾後的胜肽對於4種醫院內病原菌 (Acinetobacter baumannii、Klebsiella pneumoniae、Staphylococcus aureus及Staphylococcus epidermidis) 的MIC/MBC，以及這些胜肽對於大鼠或狗紅血球細胞的溶血活性。接著，我們挑選出展現最佳選擇性 (低MIC/MBC與低溶血活性) 的胜肽，測試它們對人類胚胎腎細胞 (HEK293) 的細胞毒性，並測試這些胜肽在大鼠血漿中的穩定性，以判斷胜肽是否易被血漿中的蛋白酶降解，同時也利用大鼠的全血測試胜肽在血液中的殺菌能力與速度。最終，我們以薄層層析分析細菌細胞膜的磷脂質組成，藉此實驗幫助找出細菌細胞膜磷脂質成分與抗菌活性之間的關係。 根據本研究的實驗結果，我們總結出將胜肽的N端以較長鏈的醯基修飾會增加溶血活性並且降低抗菌效果。在本研究所有設計的胜肽中，將序列修短的pepD3、換成D-form胺基酸的pepdD2以及將leucine換成isoleucine的pepI2表現出較好的抗菌活性和較低的溶血活性。pepdD2在血漿中最穩定，pepI2對HEK293的細胞毒性最低。在未來的研究中，我們將著重於pepD3、pepdD2、pepI2，評估此三條胜肽在活體內的功效和毒性，並測試它們是否同樣對抗藥性細菌展現出抗菌活性。 | zh_TW |
| dc.description.abstract | Recently, the overuse of traditional antibiotics makes the emergence of antibiotic-resistant bacterial strains. Unfortunately, there are not enough new drugs in the pharmaceutical pipeline to keep pace with drug-resistant bacterial development. Thus, the development of an effective novel class of antibiotics is an urgent need. Antimicrobial peptides (AMP) is considered as one of the most promising candidates for a novel class of antibiotics. In our previous investigation, we designed five cationic AMPs. All of them composed of 18 amino acids with different hydrophobic/hydrophilic amino acid distribution. After a preliminary antimicrobial test (Minimal Inhibitory Concentration/ Minimal Bactericidal Concentration test, MIC/MBC test), we chose the one which showed the best antimicrobial activity and then modified this peptide with different methods, such as decreasing peptide length, replacing amino acids with the ones with similar property, changing the N-terminal capping group, using D-form amino acids or inserting peptoid structure. We tested the MIC/MBC of these modified peptides against four nosocomial pathogens (Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus and Staphylococcus epidermidis) and the hemolysis of these peptides against rat or dog red blood cells. After that, we chose the ones that showed the best selectivity (low MIC/MBC and hemolysis) and following test their cytotoxicity to human embryonic kidney cells (HEK293). We also tested their stability in rat plasma to evaluate whether these peptides easily degraded by plasma protease. Besides, we also used rat whole blood to evaluate bactericidal ability and time-kill kinetics of peptides in blood environment. Finally, we used thin-layer chromatography to analyze the lipid composition of the bacterial cytoplasmic membrane. From this test, we can find out the relationship between bacterial membrane lipid composition and antimicrobial activity. Based on our data, we conclude that longer chain-length of the acyl group at N-terminus increased hemolysis activity and decreased antimicrobial activity. Among all the designed peptides, pepD3 (shorter length), pepdD2 (D-form peptide), and pepI2 (replace Leu with Ile) displayed better antimicrobial activity and lower hemolysis. pepdD2 is the most stable peptide in plasma. pepI2 has the lowest cytotoxicity to HEK293 cells. In the future, we will focus on pepD3, pepdD2, and pepI2 to evaluate their in vivo efficacy, in vivo toxicity, and test whether they are effective against antimicrobial-resistant bacteria. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T00:48:49Z (GMT). No. of bitstreams: 1 U0001-2411202001115700.pdf: 9399721 bytes, checksum: fb9c38b8595e6db42d190269f8cf08f5 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 目錄 口試委員會審定書 i 誌謝 ii 中文摘要 iv Abstract vi 縮寫表 Abbreviations viii 圖目錄 xvi 表目錄 xviii 第一章 緒論 1 1-1 抗菌胜肽簡介 1 1-2 抗菌胜肽之分類 3 1-2-1 α螺旋抗菌胜肽 (α-helices AMPs) 3 1-2-2 β摺板抗菌胜肽 (β-Sheet AMPs) 5 1-2-3 具延展性/隨機螺旋結構之抗菌胜肽 (extended/random-coil structure) 5 1-3 抗菌胜肽之作用機制 7 1-3-1 選擇毒性 (selective toxicity) 7 1-3-2 Two-state model 9 1-3-3 Shai–Huang–Matsuzaki 模型 9 1-3-4 細胞死亡的機制 (mechanisms of cell death) 11 1-4 抗菌胜肽在臨床上的應用 13 1-4-1 抗菌胜肽藥物介紹 13 1-4-2 發展抗菌胜肽於臨床上之應用所需面臨的挑戰 20 1-5 常見的醫院感染性細菌 21 1-6 研究目的與實驗設計 24 第二章 材料與方法 30 2-1 材料 30 2-1-1 化學藥品 30 2-1-2 細菌/細胞培養藥品 31 2-1-3 耗材 32 2-1-4 菌株/細胞株/全血 33 2-1-5 儀器 33 2-2 方法 35 2-2-1 抗菌胜肽合成 35 2-2-1-1 以PS3胜肽合成儀自動合成胜肽 36 2-2-1-2 手動合成peptide-peptoid hybrid 37 2-2-1-3 胜肽從固相樹脂上切下並去除保護基 (cleavage) 40 2-2-2 抗菌胜肽純化 40 2-2-3 細菌菌數測定 41 2-2-4 抗菌活性測試 (MIC/MBC ; 最低抑制濃度/最低殺菌濃度) 43 2-2-4-1 MIC (Minimal Inhibitory Concentration ; 最低抑制濃度) 測定 44 2-2-4-2 MBC (Minimal Bactericidal Concentration ; 最低殺菌濃度) 測定 46 2-2-5 溶血活性測試 (hemolytic assay) 47 2-2-6 細胞培養 49 2-2-6-1 解凍細胞 50 2-2-6-2 細胞繼代 50 2-2-6-3 冷凍細胞 50 2-2-6-4 細胞計數 51 2-2-7 細胞存活率測試 51 2-2-8 血漿中穩定性測試 53 2-2-9 細菌細胞膜脂質組成分析 55 2-2-9-1 細胞膜脂質萃取 55 2-2-9-2 以薄層層析分析脂質組成 55 2-2-10 殺菌時間動力學分析 (time-kill kinetic analysis) 57 第三章 結果 60 3-1 胜肽鏈長與抗菌活性及溶血活性之關係 60 3-2 同性質胺基酸之替換與鏡像異構物之替換對抗菌活性與溶血活性之影響 62 3-3 利用不同長度的羧基修飾胜肽對抗菌活性與溶血活性之影響 67 3-3-1 以長鏈脂肪酸修飾pepD2 67 3-3-2 以短鏈飽和羧酸修飾pepD3 72 3-4 使用peptide/peptoid hybrid對抗菌活性與溶血活性之影響 76 3-5 使用BBHBBHHBBH之胺基酸排列方式對抗菌活性與溶血活性之影響 80 3-6 細胞毒性測試 82 3-7 血漿中穩定性測試 84 3-8 以薄層層析分析細菌細胞膜磷脂質組成 87 3-9 殺菌時間動力學分析 (time-kill kinetic analysis) 89 第四章 討論 94 第五章 未來展望 100 參考文獻 101 附錄 112 | |
| dc.language.iso | zh-TW | |
| dc.title | 可用於對抗人類病原菌的抗菌胜肽之設計及應用 | zh_TW |
| dc.title | Design and application of antimicrobial peptides against human pathogens | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 109-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.author-orcid | 0000-0002-6433-4160 | |
| dc.contributor.oralexamcommittee | 鄭秋萍(Chiu-Ping Cheng),陳志毅(Jyh-Yih Chen),邱政洵(Cheng-Hsun Chiu) | |
| dc.subject.keyword | 抗菌胜肽,院內感染性細菌,鮑氏不動桿菌,克雷伯氏肺炎菌,金黃色葡萄球菌,表皮葡萄球菌,抗生素抗藥性細菌, | zh_TW |
| dc.subject.keyword | Antimicrobial peptides (AMPs),nosocomial pathogen,A. baumannii,K. pneumoniae,S. aureus,S. epidermidis,antimicrobial-resistant bacteria, | en |
| dc.relation.page | 138 | |
| dc.identifier.doi | 10.6342/NTU202004350 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2020-11-27 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-12-01 | - |
| 顯示於系所單位： | 生化科學研究所 | |
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