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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱浩傑 | |
| dc.contributor.author | Jung-Hsin Lo | en |
| dc.contributor.author | 羅榮新 | zh_TW |
| dc.date.accessioned | 2021-06-16T08:25:36Z | - |
| dc.date.available | 2016-02-25 | |
| dc.date.copyright | 2014-02-25 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-01-22 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58684 | - |
| dc.description.abstract | 傳染性疾病威脅著人類的生命，傳染病的控管也對全世界的醫療、公共衛生與經濟上造成重大的負擔。其中胞內細菌的感染症容易造成持續性感染以及抗藥性的產生，因研究指出胞內細菌在宿主細胞的細胞膜屏障下，難以被抗生素完全消滅。AR-12 (a.k.a. OSU-03012)原先是作為抗癌的藥物，先前我們發現AR-12能夠藉由作用在巨噬細胞來清除胞內細菌，而非直接毒殺細菌；其抑菌能力使得AR-12有潛力成為一種治療胞內細菌感染的藥物。我們進一步評估AR-12與胺基醣苷類抗生素的合併治療對胞內細菌感染的效果，因胺基醣苷類抗生素本身對於細胞內沙門氏桿菌與耶爾森氏桿菌這類胞內細菌的抑菌能力不佳。由細胞實驗的結果發現，在AR-12與胺基醣苷類抗生素的合併處理下，不僅能夠有效抑制巨噬細胞內的胞內細菌，同時能夠抑制細胞外細菌之增生。接著我們發現AR-12對巨噬細胞內的鼠傷寒沙門氏桿菌或腸炎耶爾森氏桿菌等胞內細菌皆有抑制的效果，卻對於大腸上皮細胞內該兩種胞內細菌皆不具抑制的能力，因此AR-12的抑菌能力取決於宿主細胞的類型，並對不同的胞內細菌具有療效。我們在動物實驗的結果更發現到，對受到鼠傷寒沙門氏桿菌感染的小鼠同時給予AR-12與胺基醣苷類抗生素作合併治療，能夠有效提升小鼠的存活率，而只投予小鼠胺基醣苷類抗生素則沒有顯著的療效。此外，我們進一步分析受到鼠傷寒沙門氏桿菌感染後的巨噬細胞在AR-12的作用下，其全基因表現上的變化，以探討AR-12的作用機制。總之我們以AR-12作為範例，證實以宿主為導向的抗細菌藥物可作為胺基醣苷類抗生素的佐劑，來有效治療胞內細菌所引發的感染症。 | zh_TW |
| dc.description.abstract | Infectious diseases threaten lives of human and cause a heavy burden on medicine, public health, and economy worldwide. Infection caused by intracellular bacteria, which are shown to be protected from antibiotics by cellular membranes and are therefore difficult to be eliminated completely, often causes persistent infection as well as the development of drug resistance. AR-12 (a.k.a. OSU-03012), which was originally developed as an anti-cancer drug, has been shown to be capable of eliminating intracellular bacteria within macrophages through targeting on host cells rather than killing bacteria directly. The novel antibacterial activity of AR-12 renders it a potential drug for the treatment of intracellular bacterial infection. Here, we assessed the combinatory effect of AR-12 with aminoglycosides, which have been shown to exhibit poor activity against intracellular bacteria, including Salmonella and Yersinia. The results of in vitro cell-based experiments indicated that combined treatments of AR-12 and aminoglycosides suppress not only intracellular bacteria in macrophages but also those reside extracellularly. Subsequent results suggest that the antimicrobial activity of AR-12 is cell-type specific, not bacteria-specific as both Salmonella Typhimurium and Yersinia enterocolitica within macrophages are susceptive to AR-12 while those residing in colon epithelial cells are not. On top of that, in vivo assessment also showed that combined administration of AR-12 and aminoglycosides can significantly improve the survival of S. Typhimurium-infected Balb/c mice in comparing to those received aminoglycosides alone. In addition, we further analyzed the whole genomic expression profiles of Salmonella-infected cells under AR-12 treatment to study the action mechanism. Altogether, AR-12 represents a proof of principle that the host-directed antimicrobial drug can act as an adjuvant of aminoglycoside antibiotics for the treatment of infection caused by intracellular bacteria. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T08:25:36Z (GMT). No. of bitstreams: 1 ntu-103-R99424006-1.pdf: 4703147 bytes, checksum: f8aad41c34570d1968eaac5000ead1d6 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 ii ABSTRACT iii CONTENTS iv 1. Introduction 1 1.1 Intracellular Bacterial Infection and the Difficulties in Clinical Treatment 2 1.2 Host-directed Strategy Against Intracellular Bacteria 3 1.3 The Host-directed Antibacterial Drug “AR-12” 4 1.4 Combination Therapy of AR-12 and Aminoglycosides 5 1.5 Models of Intracellular Bacteria for This Study 5 1.5.1 Salmonella enterica 5 1.5.2 Yersinia enterocolitica 7 1.6 Specific Aims 7 2. Materials and Methods 8 2.1 Bacteria Strains and Culture Condition 9 2.2 Cell Lines and Culture Condition 9 2.3 Drugs and Reagents 10 2.4 Cell Viability Assay 10 2.5 Minimum Inhibitory Concentration Assay 10 2.6 Preparation of Bacteria for Infection of Cells and Mice 11 2.7 Bacteria Growth Analysis of Salmonella Typhimurium in Cell Culture Using Colony Formation Unit Assay 11 2.8 Bacteria Growth Analysis of Yersinia enterocolitica in Cell Culture Using Colony Formation Unit Assay 13 2.9 Extracellular Growth Inhibition Assay 13 2.10 Analysis of Entry of Aminoglycosides into Macrophages 14 2.11 In Vivo Assessment of Drug Efficacy Against Salmonella Typhimurium Infection in Balb/c Mice 14 2.12 RNA Isolation and Expression Microarray Experiment 15 2.13 Data Processing of Expression Microarray Results 17 2.14 Validation of Gene Expression by Real-time PCR 17 2.15 Statistical Analysis 19 3. Results 20 3.1 Cytotoxicity of AR-12 to Cell Cultures 21 3.2 AR-12 Suppresses Salmonella Typhimurium inside Macrophages without Killing Bacteria Directly 21 3.3 AR-12 Suppresses Yersinia enterocolitica inside Macrophages without Killing Bacteria Directly 22 3.4 AR-12 Shows No Inhibitory Effect Against Intracellular Salmonella Typhimurium in Colon Epithelial Cells 23 3.5 AR-12 Shows No Inhibitory Effect Against Intracellular Yersinia enterocolitica in Colon Epithelial Cells 24 3.6 Combined Treatments of AR-12 and Aminoglycosides Suppress both Extracellular and Intracellular Salmonella Typhimurium within Macrophages 25 3.7 The Combinatory Effect of AR-12 Is Not Through Enhancing the Aminoglycosides’ Antibacterial Activity, or Facilitating the Accumulation of Aminoglycosides within Macrophages 26 3.8 Combination of Aminoglycosides and AR-12 Improves the Survivals of Salmonella-infected Balb/c Mice 28 3.9 Expression Microarray Analysis and Real-time PCR Validation of Candidate Genes 29 4. Discussion 31 4.1 Combination Therapy of AR-12 with Aminoglycosides In Vitro and In Vivo 32 4.2 Distinct Effects of AR-12 on Intracellular Bacteria in Different Types of Cells 34 4.3 Genes Regulated in AR-12 Treatment 35 4.4 Conclusion and Future Prospects 37 5. References 38 6. Tables 48 Table 1. AR-12 does not enhance the antibacterial activity of aminoglycosides against Salmonella Typhimurium. 49 Table 2. AR-12 does not facilitate entry of aminoglycosides into macrophages. 50 Table 3. Candidate genes sorted in expression microarray 51 Table 4. Real-time PCR validation of candidate genes 52 7. Figures 53 Figure 1. Cytotoxicity of AR-12. 54 Figure 2. AR-12 inhibits intracellular growth of S. Typhimurium in macrophages. 55 Figure 3. Direct AR-12 treatment on S. Typhimurium. 57 Figure 4. AR-12 inhibits intracellular growth of Y. enterocolitica in macrophages. 59 Figure 5. Direct AR-12 treatment on Y. enterocolitica. 60 Figure 6. No significant inhibitory effect of AR-12 on intracellular growth of S. Typhimurium in epithelial cell lines. 62 Figure 7. No significant inhibitory effect of AR-12 on intracellular growth of Y. enterocolitica in colon epithelial cells. 63 Figure 8. Combined treatment of gentamicin and AR-12 inhibits S. Typhimurium in macrophages. 64 Figure 9. Dose-dependent inhibitory effect of aminoglycosides combined with AR-12 on S. Typhimurium in macrophages. 66 Figure 10. Combined administration of aminoglycosides and AR-12 improves the survival of S. Typhimurium-infected mice 68 Figure 11. Relative expression of candidate genes at 6 hours of treatment by real-time PCR 70 Figure 12. Relative expression of candidate genes at 8 hours of treatment by real-time PCR 72 8. Appendix 74 Supplementary Table 1. Primers for real-time PCR reaction 75 Supplementary Figure 1. Effect of AR-12 dissolved in 5% captisol normal saline in vitro 76 | |
| dc.language.iso | en | |
| dc.subject | 胞內細菌 | zh_TW |
| dc.subject | 抗微生物製劑 | zh_TW |
| dc.subject | 合併藥物 | zh_TW |
| dc.subject | intracellular bacteria | en |
| dc.subject | antimicrobial agent | en |
| dc.subject | drug combination | en |
| dc.title | 評估以宿主為標的之抗胞內細菌感染藥物AR-12 | zh_TW |
| dc.title | Evaluation of a Host-Directed Antimicrobial Drug AR-12 Against Intracellular Bacterial Infection | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧麗珍,蕭崇瑋,陳昌熙,顏伯勳 | |
| dc.subject.keyword | 胞內細菌,抗微生物製劑,合併藥物, | zh_TW |
| dc.subject.keyword | intracellular bacteria,antimicrobial agent,drug combination, | en |
| dc.relation.page | 76 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-01-22 | |
| 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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