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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱浩傑(Hao-Chieh Chiu) | |
| dc.contributor.author | Chieh-Hsien Lu | en |
| dc.contributor.author | 呂杰憲 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:43:33Z | - |
| dc.date.available | 2025-08-17 | |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-17 | |
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Ther., 1985. 27(1): p. 1-35. 64. Chopra, I., et al., Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev, 2001. 65(2): p. 232-60 ; second page, table of contents. 65. Abdollahi, M., et al., Chloramphenicol, in Encyclopedia of Toxicology (Third Edition), P. Wexler, Editor. 2014, Academic Press: Oxford. p. 837-840. 66. Sato, K., et al., Antibacterial activity of ofloxacin and its mode of action. Infection, 1986. 14 Suppl 4: p. S226-30. 67. Wehrli, W., et al., Rifampin: mechanisms of action and resistance. Rev Infect Dis, 1983. 5 Suppl 3: p. S407-11. 68. Ament, P.W., et al., Linezolid: its role in the treatment of gram-positive, drug-resistant bacterial infections. Am Fam Physician, 2002. 65(4): p. 663-70. 69. Champney, W.S., et al., Macrolide antibiotics inhibit 50S ribosomal subunit assembly in Bacillus subtilis and Staphylococcus aureus. Antimicrob. Agents Chemother., 1995. 39(9): p. 2141-4. 70. 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Ardebili, A., et al., Effect of Efflux Pump Inhibitor Carbonyl Cyanide 3-Chlorophenylhydrazone on the Minimum Inhibitory Concentration of Ciprofloxacin in Acinetobacter baumannii Clinical Isolates. Jundishapur J Microbiol, 2014. 7(1): p. e8691. 77. Vaara, M., et al., Agents That Increase the Permeability of the Outer-Membrane. FEMS Microbiol. Rev., 1992. 56(3): p. 395-411. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79095 | - |
| dc.description.abstract | 金黃色葡萄球菌(Staphylococcus aureus)是身體表面菌相中常見的一員，約出現於30%的人口之中，常造成伺機性感染，症狀可從輕微的皮膚感染到較為嚴重的菌血症。隨著對大多數抗生素有抗藥性的抗甲氧苯青黴素金黃色葡萄球菌methicillin-resistant Staphylococcus aureus (MRSA)的出現與傳播，金黃色葡萄球菌感染症已成為全球性的健康議題，凸顯出新穎抗金黃色葡萄球菌藥物開發的重要性。在我們先前的研究中，從抗癌藥物蕾莎瓦(Nexavar；sorafenib)的衍生物篩選出了一個小分子化合物SC5005，於體外體內試驗中皆展現了良好的抗菌能力，並發現SC5005會造成細菌膜的去極化，甚至造成通透性的增加以達到殺菌的效果。爾後在優化SC5005於動物實驗的劑型時，意外發現其與特定天然物NP7合併使用後可大幅提升抑菌效果達8000倍。在這次的研究中，我們通過殺菌效力評估試驗測試SC5005與NP7合併使用後抗細菌休眠細胞的能力，結果表明合併使用後可在短時間內達到完全殺菌的效果，此外其還可以穿過細菌生物膜殺滅其內部的休眠細胞，並在MRSA皮膚感染模型中表現出顯著的抗菌活性。而此SC5005與NP7的協同作用是屬於細菌特異性的，因為在存在NP7的情況下SC5005的細胞毒性並不會隨之增加，之後的研究中指出SC5005會幫助NP7對細菌造成殺傷效果，並發現細菌內部的氧化反應扮演了相當重要的角色。接著我們進一步修飾SC5005的結構，以尋找並評估更具有潛力的化合物。在利用Time-killing assay測試一系列的SC5005衍生物與NP7的協同殺菌能力後，發現衍生物SC5178以及SC5103在與NP7合併使用下，展現出比SC5005更好的協同殺菌效果。鑑於SC5005的細胞毒性並不會因為加入NP7而有顯著的增加，此一特殊的協同殺菌活性，提供了一個開發治療抗甲氧苯青黴素金黃色葡萄球菌感染症藥物的新方向。 | zh_TW |
| dc.description.abstract | Staphylococcus aureus is colonized on approximately 30% of the human population. It is also an opportunistic pathogen, and infections can cause disease from minor skin infections to severe bacteremia. Moreover, the emergence of methicillin-resistant Staphylococcus aureus (MRSA) with resistance to most antibiotics has become a serious threat worldwide. Thus, the development of a novel antibacterial agent against MRSA has been an urgent need for public health. In our previous study, we identified a novel small-molecule compound named SC5005, which is a derivative of the anti-cancer drug sorafenib (Nexavar). SC5005 exhibited high antibacterial activity at in vitro and in vivo assays. Our results indicated that SC5005 can cause membrane depolarization and increase permeability of S. aureus membrane. While developing SC5005’s formulation for the in vivo test, we unexpectedly found a natural product, NP7, that can significantly enhance SC5005’s antibacterial activity to more than 8,000-fold. The combination of SC5005 and NP7 can completely eradicate MRSA and planktonic persister cells in the time-killing assay. Furthermore, this combination is also capable of penetrating into the biofilm to kill persisters inside, and exhibited a significant antibacterial activity in the MRSA skin infection model. The synergistic effect of SC5005 with NP7 is bacteria-specific as SC5005’s cytotoxicity is not increased in the presence of NP7. Subsequent investigation indicated that SC5005 increased MRSA susceptibility to NP7, and the oxidative stress in the bacteria is essential to this synergistic bactericidal effect of NP7 and SC5005. To further optimize the bacterial killing activity of this combination, a series of SC5005 derivatives were designed and synthesized. The synergistic killing activity of SC5005 derivatives with NP7 was assessed using a time-killing assay. The screening identified SC5103 and SC5178 which showed a better killing activity in combined with NP7 than that of SC5005. Altogether, our findings showed that the synergistic bactericidal activity of SC5005 and NP7 is promising and could be further exploited as a new therapeutic against MRSA. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:43:33Z (GMT). No. of bitstreams: 1 U0001-1708202016045900.pdf: 4453758 bytes, checksum: 234289270bfab01c1d4698f613265840 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 致謝 I 中文摘要 III Abstract IV Contents 1 1. Introduction 8 1.1 Staphylococcus aureus 9 1.2 The global threat of methicillin-resistant Staphylococcus aureus 10 1.3 The strategy of repurposing non-antibiotics to bacterial infections 13 1.4 The novel small-molecule antibacterial compound “SC5005” 14 1.5 The synergistic effect of SC5005 with nature products 14 2. Materials and Methods 16 2.1 Bacteria and culture condition 17 2.2 Medium 17 2.3 Chemicals 18 2.4 Antibacterial assays 18 2.5 Cell culture 19 2.6 Anti-proliferative assay 19 2.7 Time-kill assay 20 2.8 Biofilm eradication assay 21 2.9 Calcein leakage assay 22 2.10 Persisters assay 24 2.11 Membrane potential assay with flow cytometry 24 2.12 Checkerboard assay 25 2.13 In vivo infection assay 26 2.14 ROS detection 29 2.15 Statistical analysis 30 3.Results 31 3.1 The action mechanism of SC5005 against S. aureus 32 3.2 The antibacterial activity and compound stability of SC5005 derivatives 37 3.3 SC5005 didn’t show synergistic effect with other antibiotics 39 3.4 The fast-eradicating activity of the combination of SC5005 and NP7 against planktonic MRSA persisters. 40 3.5 The synergistic mechanism of the combination of SC5005 and NP7 against S. aureus. 44 3.6 The derivatives of SC5005 showed better antibacterial activity synergized with NP7 46 3.7 Evaluate the in vivo efficacy of SC5005 and its optimal derivatives in combined with NP7 47 4. Discussion 49 4.1 SC5005 showed no antibacterial activity on Gram-negative bacteria. 50 4.2 The antagonism effect on biofilm eradication activity of SC5005 combined with NP7 51 4.3 The SC5005 combined with NP7 can’t show the robust bactericidal effect at in vivo 51 4.4 The antagonism effect on the combination of SC5005 and valinomycin 52 4.5 Conclusion and future work 52 5. References 54 6. Tables 67 Table 1. The effect of magnesium on the antibacterial activity of SC5005 against S. aureus. 68 Table 2. Anti-bacterial activity of SC5005 against Bacillus subtilis lacking different phospholipid. 69 Table 3. Antibacterial activity of SC5005 and SC5005 derivatives in medium with various percentage of FBS. 70 Table 4. NP7 increases SC5005’s antibacterial activity. (The data is adapted from Chia-Min Yuan’s master thesis) 71 Table 5. Anti-proliferative activity of SC5005 combined with NP7 toward different human epithelial cell lines. (The data is adapted from Chui-Hian Lim’s master thesis) 73 Table 6. Antibacterial activity of SC5005 combined with different forms of NP7. 74 Table 7. Biofilm eradicating activity of antibiotics, SC5005, and SC5005 combined with NP7. 75 Table 8. Antibacterial activity and synergistic killing activity of SC5005 derivatives against MRSA ATCC33592. 76 7. Figures 77 Figure 1. SC5005 affects different pathways of S. aureus without detectable resistance. (The data is adapted from Han-Chu Chang’s master thesis) 78 Figure 2. Percentage of membrane-compromised cell after SC5005 treatment. (The data is adapted from Chui-Hian Lim’s master thesis) 79 Figure 3. The membrane potential of S. aureus treated valinomycin, CCCP and SC5005. 80 Figure 4. Effect of SC5005 on artificial liposome composed of different phospholipids, which mimics the membrane of S. aureus. 81 Figure 5. Anti-proliferative activity of SC5005 and SC5103 in culture medium with different concentration of FBS 82 Figure 6. SC5103 exhibited a better efficacy in the MRSA skin infection model than SC5005. 83 Figure 7. The antibacterial activity of SC5005 in combined with antibiotics. (Part of the data is adapted from Chia Min Yuan’s master thesis) 84 Figure 8. The killing kinetic of SC5005 combined with NP7 on MRSA ATCC33592 85 Figure 9. The killing kinetic of SC5005 combined with NP7 against MRSA persisters. 86 Figure 12. The synergistic antibacterial activity of SC5005 and NP7 can be inhibited by a variety of antioxidants. (The data is adapted from Chui-Hian Lim’s master thesis) 91 Figure 13. The intracellular ROS level of MRSA USA300 treated with SC5005 or SC5005 combined with NP7 92 Figure 14. Antibacterial activity and cytotoxicity of SC derivatives in combined with NP7 94 Figure 15. The membrane potential of S. aureus treated with SC5005, SC5178, SC5103 or CCCP 95 Figure 16. Effect of intraperitoneal administration of SC5005 on the survival of MRSA-infected mice 96 Figure 17. The efficacy of SC5005, SC5178 and SC5103 in combined with NP7 in the MRSA USA300 skin infection model 97 8. Supplementary 98 Table S1. Antibacterial spectrum of SC5005 (The data is adapted from Han-Chu Chang’s master thesis) 99 Table S2. The MICs of SC5005 and CCCP against MSSA NCTC8325 in the presence of menaquinone-4 (MK-4) 100 Table S3. MICs of antibiotics and SC5005 against reference strain and efflux pump deficient strains of E. coli 101 Table S4. MBEC of SC5005 against MRSA USA300 biofilm pretreated with NP7 102 Figure S1. The intracellular ATP level of S. aureus. (The data is adapted from Chia-Min Yuan’s and Sheng-Hsuan Huang’s master thesis) 103 Figure S2. The antibacterial effect of SC5005 combined with CCCP or valinomycin on MRSA USA300 104 Figure S3. The membrane potential of S. aureus treated with SC5005 or SC5005 combined MK-4. 105 | |
| dc.language.iso | en | |
| dc.subject | 協同殺菌 | zh_TW |
| dc.subject | 抗甲氧苯青黴素之金黃色葡萄球菌 | zh_TW |
| dc.subject | SC5005 | zh_TW |
| dc.subject | SC5005 | en |
| dc.subject | MRSA | en |
| dc.subject | synergistic bactericidal effect | en |
| dc.title | 探討SC5005與天然物對抗藥性金黃色葡萄球菌、休眠細胞與生物膜的協同抗菌機制 | zh_TW |
| dc.title | The synergistic mechanism of SC5005 and nature products against antibiotic-resistant Staphylococcus aureus, persisters and biofilms | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.advisor-orcid | 邱浩傑(0000-0002-8800-8474) | |
| dc.contributor.coadvisor | 鄧麗珍(Lee-Jene Teng) | |
| dc.contributor.coadvisor-orcid | 鄧麗珍(0000-0003-0104-741X) | |
| dc.contributor.oralexamcommittee | 蘇伯琦(Po-Chi Soo),陳振暐(Jenn-Wei Chen),蕭崇瑋(Chung-Wai Shiau) | |
| dc.subject.keyword | 抗甲氧苯青黴素之金黃色葡萄球菌,SC5005,協同殺菌, | zh_TW |
| dc.subject.keyword | MRSA,SC5005,synergistic bactericidal effect, | en |
| dc.relation.page | 105 | |
| dc.identifier.doi | 10.6342/NTU202003784 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-17 | |
| 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 |
| dc.date.embargo-lift | 2025-08-17 | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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