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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳穎練 | zh_TW |
| dc.contributor.author | 柯皓達 | zh_TW |
| dc.contributor.author | Hao-Tai Ko | en |
| dc.date.accessioned | 2021-07-11T15:46:29Z | - |
| dc.date.available | 2024-08-06 | - |
| dc.date.copyright | 2018-08-16 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | [1] Chang YL, Yu SJ, Heitman J, Wellington M, Chen YL. New facets of antifungal therapy. Virulence. 2017;8:222-36.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79131 | - |
| dc.description.abstract | 全世界預估約有12億人口遭受真菌性感染，新型隱球菌(Cryptococcus neoformans)和格特隱球菌(Cryptococcus gattii)可造成人類隱球菌症(cryptococcosis)，是一種每年可造成約60萬人口死亡的人體伺機性病原。然而，治療策略卻十分侷限，因為傳統藥物開發的時程緩慢，加上抗藥性菌株有逐年增加的趨勢，因此，研發創新、有效且低毒性的抗真菌藥物為論文研究之目標。透過快速且大量篩選1,018種美國食品藥物管理局核准之藥物，我們從中發現一種過去用來治療自體免疫性血小板減少性紫斑症的藥物eltrombopag在最低抑制濃度0.125至 0.5 μg/mL下具有抑制隱球菌、光滑念珠菌及皮癬菌的效果。進一步實驗結果發現，eltrombopag與鈣調磷酸酶抑制劑 FK506具有協同作用(synergistic effect)。另外也發現此藥物可以顯著干擾隱球菌重要的致病因子，例如生物膜的形成、莢膜的形成、黑色素的合成與生長於37 ºC。掃描式電子顯微鏡的結果顯示隱球菌細胞表面出現許多破碎殘體，推測施用eltrombopag可能會破壞部分細胞表面結構，此結果可能與eltrombopag為抑菌而非殺菌的特性有關係。透過RNA測序(RNA sequencing)及基因功能分類分析(Gene ontology analysis)，結果顯示受藥物處理的大部分基因群和脂質生合成、跨膜運輸及細胞膜的組成有很大的關聯，即時反轉錄聚合酶鏈式反應的結果也證實受藥物處理後的樣本，其基因表現與對照組的有顯著性差異。為了證明eltormbopag確實對隱球菌之細胞膜造成受損，我們使用propidium iodide (PI)染色方法來評估受eltrombopag處理過後的細胞膜對PI染劑的滲透性。動物模式的結果顯示1 mg/kg/day eltrombopag可以顯著降低隱球菌在小鼠腦部的菌落數，但在存活率的數據上並無顯著差異。本研究是第一篇發現eltrombopag具有抗隱球菌活性的藥物，上述研究成果認為eltrombopag除了原本對紫斑病的治療，另外也具有潛力並開發應用於臨床上治療隱球菌症。 | zh_TW |
| dc.description.abstract | About 1.2 billion people worldwide are estimated to suffer from fungal infections. Cryptococcus neoformans and Cryptococcus gattii are the major opportunistic pathogens that cause cryptococcosis and responsible for approximately 600,000 deaths annually on a global scale. However, treatments remain challenging due to limited therapeutic options, rapidly emerging drug-resistant isolates and time-consuming research and development of new drugs. In this study, our objective is to discover compounds with low toxicity but exhibit novel antifungal activity. We identified eltrombopag, a medication that had been approved for the treatment of immune thrombocytopenia (ITP), via screening a compound library containing 1,018 FDA-approved drugs. Eltrombopag is firstly demonstrated to exhibit antifungal activity against fungal pathogens, such as Cryptococcus species with minimum inhibitory concentration (MIC) at 0.125 μg/mL, Candidia glabrata at 0.25 μg/mL, and Trichophyton rubrum at 0.5 μg/mL. Meanwhile, eltrombopag showed synergistic effect with a calcineurin inhibitor FK506 against Cryptococcus species. Furthermore, we showed that eltrombopag affected cryptococcal virulence factors such as biofilm formation, capsule formation, melanin production and growth ability at 37 ºC. Assisted by scanning electron microscopy, we observed impaired cryptococcal cell surface after eltrombopag treatment which may be associated with the fungistatic effect of eltrombopag against Cryptococcus species. RNA sequencing experiments revealed that many genes involved in lipid biogenesis, membrane components and transmembrane transporter were regulated by eltrombopag and confirmed by real time RT-PCR. To validate that the function of cell membrane was impaired, we assessed membrane permeability by propidium iodide staining. In the murine model of cryptococcosis, the results of fungal burden revealed that 1 mg/kg/day eltrombopag could significantly reduce cryptococcal colony formation units (CFU) in the brains, but the studies of survival rate did not show any difference in all treatments. Our data suggests that eltrombopag may be a promising antifungal agent against cryptococcal infections in addition to its original treatment of ITP. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:46:29Z (GMT). No. of bitstreams: 1 ntu-107-R05633014-1.pdf: 3278041 bytes, checksum: 642e74de03480270c013ce8dc5e34654 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | Table of Contents
口試委員會審議書 i 誌謝 ii 摘要 iii Abstract iv Table of Contents vi List of Figures viii List of Tables ix 1. Introduction 1 1.1 Fungal infection: Cryptococcosis 1 1.2 Antifungal drug research and development 2 1.3 Drug repurposing 3 1.4 FDA-approved drug: Eltrombopag 4 2. Materials and methods 5 2.1 Strains, growth media and drugs 5 2.2 Drug library screening 5 2.3 Determination of minimum inhibitory and fungicidal concentrations 6 2.4 Determination of fractional inhibitory concentration indices 6 2.5 Growth kinetics assays 7 2.6 Disk diffusion assays 8 2.7 XTT-reduction assay for biofilm formation 8 2.8 Effect of eltrombopag on capsule formation 8 2.9 Melanization assays 9 2.10 Effect of eltrombopag on cellular ultrastructure 9 2.11 RNA-sequencing experiments 10 2.12 Quantitative real-time RT-PCR 11 2.13 Effect of eltrombopag on cell membrane function 12 2.14 In vivo model of systemic cryotococcosis and antifungal treatment 12 3. Results 14 3.1 Screening results of compound libraries 14 3.2 Eltrombopag exhibits novel antifungal activity against Cryptococcus species 14 3.3 Eltrombopag is fungistatic against C. neoformans and more efficient at elevated temperature 15 3.4 Eltrombopag displays synergy with the calcineurin inhibitor FK506 against Cryptococcus species 15 3.5 Eltrombopag impairs biofilm formation of C. neoformans 16 3.6 Eltrombopag reduces capsule formation of Cryptococcus species 17 3.7 Eltrombopag inhibits melanization of C. neoformans 18 3.8 Effect of eltrombopag on cellular ultrastructure of Cryptococcus species 18 3.9 Hypothetical mode of action of eltrombopag 19 3.10 Effect of eltromboapg on cell membrane integrity of Cryptococcus species 20 3.11 Eltrombopag displays promising antifungal activity in a murine model of systemic cryptococcosis 20 4. Discussion 22 4.1 Eltrombopag serves as a promising anti-Cryptococcus agent 22 4.2 The combination therapy between eltrombopag and calcineurin inhibitor offers potential therapeutic strategy for cryptococcal infections 22 4.3 The proposed antifungal mechanisms of eltrombopag 23 4.4 Safety issues and potential use of eltrombopag in treating cryptococcosis 25 5. Conclusion 26 6. References 48 7. Appendix 54 List of Figures Figure 1. Growth kinetics of Cryptococcus species was dose-dependent and temperature sensitive in the presence of eltrombopag.. 27 Figure 2. Eltrombopag exhibits synergistic effects with FK506 against C. neoformans H99 and C. gattii R265 28 Figure 3. Eltrombopag reduced cryptococcal biofilm formation 29 Figure 4. Capsule formation defects of C. neoformans H99 and C. gattii R265 cells after eltrombopag treatment 30 Figure 5. Eltrombopag inhibits melanization of C. neoformans H99 31 Figure 6. The effect of eltrombopag on the ultrastructure of C. neoformans H99 and C. gattii R265 32 Figure 7. Genes up- and downregulated after eltrombopag treatment in C. neoformans H99 33 Figure 8. Real-time RT PCR was used to confirm genes after eltrombopag treatment in C. neoformans H99 34 Figure 9. Eltrombopag disrupts the cell membran permeability of Cryptococcus species. 35 Figure 10. Eltrombopag at the dose of 1 mg/kg reduces the fungal burden in the brain organs but exhibits limited anti-cryptococcal activity in survival curve 36 Figure S1. RNA sequencing data were uploaded to Gene Expression Omnibus and the accession number GSE115570 was obtained 37 List of Tables Table 1. Fungal strains used in this study. 38 Table 2. MICs and MFCs of eltrombopag for multiple fungal pathogens. 39 Table 3. Eltrombopag exhibited synergistic antifungal activity with FK506 against Cryptococcus species. 40 Table 4. Genes regulated by eltrombopag in Cryptococcus neoformans H99 41 Table S1. The antifungal screening list of 60 FDA-approved drugs from drug libraries. 44 Table S2. Oligonucleotide primers used in this study. 47 | - |
| dc.language.iso | en | - |
| dc.subject | Eltrombopag | zh_TW |
| dc.subject | 舊藥新用 | zh_TW |
| dc.subject | 抑菌作用 | zh_TW |
| dc.subject | 隱球菌 | zh_TW |
| dc.subject | 鈣調磷酸?抑制劑 | zh_TW |
| dc.subject | antifungal | en |
| dc.subject | Cryptococcus | en |
| dc.subject | Eltrombopag | en |
| dc.subject | calcineurin inhibitor | en |
| dc.subject | drug repurposing | en |
| dc.title | 血小板生成素受體致效劑eltrombopag之新穎抗隱球菌活性 | zh_TW |
| dc.title | The thrombopoietin receptor agonist eltrombopag exhibits novel anti-Cryptococcus activity | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 陳宜君;曾祥洸;蕭崇瑋 | zh_TW |
| dc.contributor.oralexamcommittee | ;; | en |
| dc.subject.keyword | Eltrombopag,舊藥新用,抑菌作用,隱球菌,鈣調磷酸?抑制劑, | zh_TW |
| dc.subject.keyword | Eltrombopag,drug repurposing,antifungal,Cryptococcus,calcineurin inhibitor, | en |
| dc.relation.page | 69 | - |
| dc.identifier.doi | 10.6342/NTU201802416 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-08-07 | - |
| dc.contributor.author-college | 生物資源暨農學院 | - |
| dc.contributor.author-dept | 植物病理與微生物學系 | - |
| 顯示於系所單位： | 植物病理與微生物學系 | |
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