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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱浩傑(Hao-Chieh Chiu) | |
| dc.contributor.author | Han-Chu Chang | en |
| dc.contributor.author | 張翰築 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:48:10Z | - |
| dc.date.copyright | 2015-09-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-07-21 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18000 | - |
| dc.description.abstract | 抗甲氧苯青黴素之金黃色葡萄球菌具有對抗大多數抗生素之能力，導致治療上非常棘手，對於人類健康而言是個很嚴重的威脅，因此必須發展新穎的抗葡萄球菌藥物。在我們的研究中發現原本應用於治療癌症的酪胺酸激酶抑制劑蕾莎瓦(Nexavar; sorafenib)具有抑制抗藥性較低的金黃色葡萄球菌能力，但對於抗甲氧苯青霉素之金黃色葡萄球菌卻沒有抑制效果。為了降低蕾莎瓦對細胞之毒性且保留抑制細菌之能力，我們以蕾莎瓦衍生物抑菌能力以及細胞毒性進行篩選，發現SC-78與SC-5005不只能夠抑制臨床分離的多重抗藥葡萄球菌，對於抗萬古黴素之腸球菌以及大多數具有致病性的革蘭氏陽性菌皆有抑制效果，但無法抑制革蘭氏陰性細菌。相較於細胞毒性極高的蕾莎瓦，SC-78與SC-5005對人類細胞株的毒性降低許多，其中又以SC-5005具有較高的選擇性(抑制百分之五十細胞增生之藥物濃度/最低抑制細菌濃度)，比較適合作為抗細菌藥物。此外，我們也使用了線蟲模式評估這兩種藥物在活體內的細胞毒性，發現SC-78具有急毒性但SC-5005沒有，因此我們選擇SC-5005進行動物實驗評估藥效。我們在動物實驗結果中發現，若給予受到全身性多重抗藥葡萄球菌感染的小鼠SC-5005治療，能夠顯著地提高小鼠的存活率。目前從巨分子合成分析法得到的結果顯示SC-5005可能作用於細菌的細胞膜上，並使用螢光染色後發現加藥處理後會造成細菌的細胞膜破損，亦造成細菌胞內ATP流失。然而即使在一百二十八倍的最小抑菌濃度下仍不會造成人類紅血球產生溶血現象。 | zh_TW |
| dc.description.abstract | Methicillin-resistant Staphylococcus aureus (MRSA) becomes a serious threat to human health because of multidrug resistance to most antibiotics used in medical treatment. Thus, it is imperative to develop a novel anti-Staphylococcus agent. In our study, we find that sorafenib (Nexavar), a tyrosine kinase inhibitor which was used in cancer therapy, can not only suppress human cell proliferation but also moderately inhibit methicillin-sensitive Staphylococcus aureus (MSSA). However, it has no inhibitory effect on MRSA. To improve sorafenib’s antibacterial activity, an in-house sorafenib-based focused compound library was synthesized and screened followed by in vitro efficacy against S. aureus and cytotoxicity to human cell line evaluation. We found that SC-78 and SC-5005 can inhibit clinically-isolated MRSAs, vancomycin-resistant Enterococci (VRE), and most pathogenic Gram-positive bacteria. Nevertheless, Gram-negative bacteria are not susceptible to these two agents. In comparison with sorafenib that possess high cytotoxicity, SC-78 and SC-5005 are less toxic to cell, and SC-5005 is more suitable for development of antibacterial agents because of much higher selectivity ratio (antiproliferative activity /antibacterial activity) than SC-78. In addition, we also assessed in vivo cytotoxicity of these two agents by C. elegans model. The results demonstrated that SC-78 possessed acute cytotoxicity, but SC-5005 didn’t. Therefore, we choose SC-5005 to evaluate the efficacy against systemic infection by MRSA in C57BL/6J mice. The survival rate of infected mice treated with SC-5005 increases significantly in contrast to control. The findings indicated that SC-5005 has potential to fight with MRSA infection. The mode of action of SC-5005 on S. aureus was unveiled by macromolecule synthesis assay, and the result pointed out that SC-5005 might act on cell membrane. After treatment, the damage to bacterial cell membrane was observed by fluorescence microscopy. Apart from that, SC-5005 also lead to leakage of intracellular ATP in bacteria. However, the agent did not cause hemolysis on human red blood cell at the concentration of 128-fold MIC against S. aureus. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:48:10Z (GMT). No. of bitstreams: 1 ntu-104-R02424023-1.pdf: 4282730 bytes, checksum: a3161f38c1ae19b467607af48bdda1ca (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 致謝 i 中文摘要 ii Abstract iii Contents v 1. Introduction 1 1.1 Staphylococcus aureus 2 1.2 Methicillin-resistant Staphylococcus aureus (MRSA) 2 1.3 Difficulties in treatment for MRSA infections 3 1.4 Strategies to develop novel antibacterial agents against MRSA 4 1.4.1 Modification of functional groups of traditional antibiotics 4 1.4.2 Identified from natural antibacterial molecules 4 1.4.3 Synthetic antimicrobial peptidomimetics (SAMPs) 5 1.4.4 Modification from existing “non-antibiotics” 5 1.5 Anti-cancer drug “Sorafenib” 6 1.6 Specific aims 6 2. Materials and Methods 7 2.1 Bacterial strains and culture conditions 8 2.2 Cell lines and culture conditions 9 2.3 Chemicals and reagents 9 2.4 Antibacterial assays 9 2.5 Antiproliferative assay 10 2.6 Time-kill assay 11 2.7 In vivo efficacy against S. aureus infection in C. elegans studies 11 2.8 In vivo efficacy against MRSA systemic infection in C57BL/6J mice studies 12 2.9 Macromolecule synthesis assay 13 2.10 Fluorescence microscopy assay for pore formation 14 2.11 Measurement of intracellular ATP levels using luciferase assay 15 2.12 Hemolytic assay 15 3. Results 17 3.1 Antibacterial activity of sorafenib and its derivatives against Staphylococcus aureus and Staphylococcus epidermidis 18 3.2 Antiproliferative activity of sorafenib and its derivatives to human cancer cell line 18 3.3 Antibacterial activity spectrum of SC-78 and SC-5005 against Staphylococcus species and clinically-isolated MRSAs 19 3.4 Antibacterial activity spectrum of SC-78 and SC-5005 against VISA and VRSA 19 3.5 Antibacterial activity spectrum of SC-78 and SC-5005 against pathogenic Gram-positive and Gram-negative bacteria 20 3.6 Time-kill assay of SC-78 and SC-5005 against S. aureus NCTC 8325 21 3.7 Drug resistance of S. aureus NCTC 8325 against SC-78 and SC-5005 22 3.8 Efficacy of SC-78 and SC-5005 against MRSA infection in C. elegans 22 3.9 Efficacy of SC-5005 against MRSA systemic infection in C57BL/6J mice 23 3.10 Efficacy of SC-5005 against VRSA systemic infection in C57BL/6J mice 24 3.11 Mode of action of SC-5005 and SC-5035 on S. aureus 24 3.12 Hemolytic activities of SC-5005 and SC-5035 on human red blood cell 25 4. Discussion 27 4.1 Sorafenib derivatives SC-78 and SC-5005 possess broad-spectrum of antibacterial activity against Gram-positive bacteria but not Gram-negative bacteria 28 4.2 SC-78, SC-5005, and SC-5035 lose in vitro suppressive effect on bacteria because of high protein binding 29 4.3 S. aureus is unable to develop resistance against SC-78 and SC-5005 30 4.4 Intraperitoneal administration of SC-5005 cannot cure all MRSA systemic infection C57BL/6J mice 30 4.5 Conclusion and future prospects 31 5. References 32 6. Tables 40 Table 1. Antibacterial activity of sorafenib and its derivatives against Staphylococcus aureus and Staphylococcus epidermidis 41 Table 2. Anti-Staphylococcus (MIC) versus antiproliferative (IC50) activities of sorafenib and its derivatives 42 Table 3. Antibacterial activity spectrum of SC-78 and SC-5005 against Staphylococcus species 43 Table 4. Antibacterial activity spectrum of SC-78 and SC-5005 against Gram-positive and Gram-negative bacteria 44 Table 5. Antibacterial activity SC-78 and SC-5005 against E. coli with outer membrane or efflux pump defect. 45 7. Figures 46 Figure 1. Time-kill assay of SC-78 and SC-5005 against S. aureus NCTC 8325 47 Figure 2. Drug resistance of S. aureus NCTC 8325 48 Figure 3. Efficacy of SC-78 and SC-5005 against MRSA infection in C. elegans. 49 Figure 4. Efficacy of SC-5005 against MRSA systemic infection in C57BL/6J mice. 51 Figure 5. Efficacy of SC-5005 against VRSA systemic infection in C57BL/6J mice. 53 Figure 6. Influence of SC-5005 and SC-5035 on S. aureus. 54 Figure 7. Pore formation on S. aureus after SC-5005 and SC-5035 treatment. 55 Figure 8. Intracellular ATP levels in S. aureus after SC-5005 and SC-5035 treatment. 56 Figure 9. Hemolytic activities of SC-5005 and SC-5035 on human red blood cell. 58 8. Supplementary 59 Table S1. Antibacterial activity of SC-78 and SC-80 derivatives, SC-5001 to SC-5045, against S. aureus 60 Table S2. Antibacterial susceptibility profile of clinically-isolated MRSAs 61 Table S3. Influence of protein on SC-78, SC-5005, and SC-5035. 64 Table S4. Solubility test of SC-5005 and antibacterial activity against S. aureus 66 | |
| dc.language.iso | en | |
| dc.title | 探討新穎的抗金黃色葡萄球菌藥物SC-5005 | zh_TW |
| dc.title | Investigation of a Novel Antibacterial Agent SC-5005 against Staphylococcus aureus | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧麗珍,蕭崇瑋(Chung-Wai Shiau),盧彥伸 | |
| dc.subject.keyword | 抗甲氧苯青黴素之金黃色葡萄球菌,蕾莎瓦,抗萬古黴素之腸球菌, | zh_TW |
| dc.subject.keyword | MRSA,Sorafenib (Nexavar),vancomycin-resistant enterococci, | en |
| dc.relation.page | 67 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2015-07-21 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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