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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱浩傑(Hao-Chieh Chiu) | |
| dc.contributor.author | Ching-Yi Yang | en |
| dc.contributor.author | 楊靖懿 | zh_TW |
| dc.date.accessioned | 2021-06-16T09:23:00Z | - |
| dc.date.available | 2021-09-12 | |
| dc.date.copyright | 2017-09-12 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-06-23 | |
| dc.identifier.citation | 1. Marseille-Luminy, C.d.I.d., et al., Bacterial manipulation of innate immunity to promote infection. Nat Rev Microbiol, 2010: p. 117-128.
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Jenkins, Loxapine Intoxication: Case Report and Literature Review. Journal of Analytical Toxicology, 2000. 24: p. 638-341. 29. Popovic, D., P. Nuss, and E. Vieta, Revisiting loxapine: a systematic review. Annals of General Psychiatry, 2015. 30. Menashe, O., et al., Aminoglycosides Affect Intracellular Salmonella enterica Serovars Typhimurium and Virchow. Antimicrobial Agents and Chemotherapy, 2008. 52: p. 920-926. 31. MAURIN, M. and D. RAOULT, Use of Aminoglycosides in Treatment of Infections Due to Intracellular Bacteria. Antimicrobial Agents and Chemotherapy, 2001. 45: p. 2977–2986. 32. Takaya, A., et al., The DnaK/DnaJ Chaperone Machinery of Salmonella enterica Serovar Typhimurium Is Essential for Invasion of Epithelial Cells and Survival within Macrophages, Leading to Systemic Infection. Infection and Immunity, 2004. 72: p. 1364–1373. 33. Denise M. Monacka, W.W.N., Stanley Falkow, Salmonella-induced macrophage death: the role of caspase-1 in death and inflammation. Microbes and Infection, 2001: p. 1201-1212. 34. Libby, S.J., et al., The Salmonella virulence plasmid spv genes are required for cytopathology in human monocyte-derived macrophages. Cell Microbiol, 2000. 2(1): p. 49-58. 35. van der Velden, A.W., et al., Salmonella pathogenicity island 1-independent induction of apoptosis in infected macrophages by Salmonella enterica serotype typhimurium. Infect Immun, 2000. 68(10): p. 5702-9. 36. Daniel Hurley, M.P.M., Séamus Fanning and Marta Martins, Salmonella–host interactions – modulation of the host innate immune system. Frontiers in Microbiology, 2014. 5. 37. LEONARD AMARAL, M.V.a.J.M., Antimicrobial Activity of Phenothiazines. In Vivo, 2004: p. 725-732. 38. Shalini Duggal, N.K., Ashish Kumar Duggal, M.S. Bhatia, Phenothiazines: hope against MDR-TB. DELHI PSYCHIATRY, 2008. 11: p. 64-68. 39. Meeta J. Advani, M.R.P.H.R., Calmodulin-like protein from M. tuberculosis H37Rv is required during infection. Scienticfic Reports, 2014. 40. Roufogalis, B.D., A.M. Minocherhomjee, and A. Al-Jobore, Pharmacological antagonism of calmodulin. Can J Biochem Cell Biol, 1983. 61(8): p. 927-33. 41. Motohashi, N., Phenothiazines and calmodulin (review). Anticancer Res, 1991. 11(3): p. 1125-64. 42. Ghezzi, P., Effects of chlorpromazine on polymorphonucleocyte-mediate activities in vivo and in vitro. Immunology, 1991: p. 138-143. 43. Replication of Salmonella enterica Serovar Typhimurium in Human Monocyte-Derived Macrophages. Infection and Immunity, 2015: p. 2661-2671. 44. Preeti Malik-Kale, C.E.J., Stephanie Lathrop, Seth Winfree, Courtney Luterbach and Olivia Steele-Mortimer, Salmonella–at home in the host cell. Frontiers in Microbiology, 2011. 45. Thiresen Govender, Y.E.C., Pradeep Kumar, Lisa C. Du Toit, Girish Modi, Dinesh Naidoo and Viness Pillay, A Novel Melt-Dispersion Technique for Simplistic Preparation of Chlorpromazine-Loaded Polycaprolactone Nanocapsules. Polymers, 2015. 7: p. 1145-1176. 46. Roos, E.M.-E., Serum levels of thioridazine in psychiatric patients and healthy volunteers. European Journal of Clinical Pharmacology, 1973. 6: p. 181-186. 47. LARSEN, L.B.H.a.N.-E., Plasma Concentrations of Perphenazine and its Sulphoxide Metabolite during Continuous Oral Treatment. Psychopharmacology, 1977. 53: p. 127-130. 48. K. K. Midha, E.M.H., G. McKay, J. W. Hubbard, E. D. Korchinski, and D. L. Keegan, Plasma concentrations of trifluoperazine following single low doses. Can Med Assoc J, 1983: p. 324. 49. Chang SS, J.J., Dysken MW, Casper RC, Janicak PG, Davis JM, Plasma levels of fluphenazine during fluphenazine decanoate treatment in schizophrenia. Psychopharmacology (Berl), 1985: p. 55-58. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59413 | - |
| dc.description.abstract | 抗生素可用於治療大部分細菌感染疾病，然而不當的濫用使得許多抗藥性的產生，而部分具有兼性胞內寄生特性的病原菌，甚至可以透過入侵宿主細胞，來逃避外在抗生素的作用，並持續在細胞內存活(例：Salmonella spp.)，更凸顯出尋找對抗多重抗藥性胞內寄生菌藥物的急迫性。本實驗中，我們以受鼠傷寒沙門氏菌感染的巨噬細胞進行篩選，發現了一個具有抑菌效力的抗精神疾病藥物─Loxapine，而本篇研究即為探討Loxapine 的抑菌能力和與抗生素組合作用的差異。首先，我們以廣大黴素(Gentamicin)與不同濃度Loxapine 共同作用。得知在4 μM下，Loxapine 不僅能夠有效抑制細菌於巨噬細胞內的增生，同時也抑制胞外細菌，使總菌量降低至百分之五十以下，而此藥的半數致死量(IC50)高達108 μM，與抑菌所需濃度相差25 倍之多，確定了抑菌效果並非細胞的死亡；而以此濃度，與其它胺基醣苷類抗生素合併處理，或改以多重抗藥性菌株為對象，也會展現出相同的抑菌效果。其次，為了確認Loxapine 抑菌作用的特異性，我們先以生長曲線實驗確定了Loxapine 並不會對沙門氏菌有直接的抑制作用；而在後續的實驗中，我們也得知Loxapine 單獨作用下會有些許的抑菌效果，對於感染的細胞也有保護的效力。而在Loxapine 與胺基醣苷類類抗生素的增益上，我們以測試巨噬細胞內抗生素的堆積以及活性來觀察，發現在這兩者Loxapine 對並無直接性的影響。最後，我們以感染了鼠傷寒沙門氏菌的BALB/c 老鼠進行實驗，結果卻發現同時給予Loxapine 與胺基糖苷類抗生素的組別，其存活率與單獨給予抗生素的組別，並無顯著性的差異，我們懷疑造成此結果的主因，可能是由於Loxapine 的血清濃度無法達到抑菌所需濃度。從前面的體外實驗中，證實了Loxapine 具有做為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共同使用。 | zh_TW |
| dc.description.abstract | Antibiotics are medicines used to treat bacterial infections. Due to the inappropriate use of antibiotics, many pathogenic bacteria resistant to multiple-antibiotic have emerged worldwide. Moreover, some facultative intracellular bacterial pathogen can evade the bactericidal effect of antibiotics by invading into host cell and survival in cytoplasm (ex. Salmonella spp.). Thus, there is an urgent need to find out an innovative therapeutic approach for diseases caused by intracellular multiple-drug resistant bacteria. Here, we used Salmonella Typhimurium ATCC14028 strain infected RAW 264.7 cell to identify an antipsychotic drug, loxapine, having the ability to be used as a new antibacterial agent. We first showed that 4μM of loxapine can lower total bacteria to less than 50% of that in control group combined with gentamicin, which was 1/27 of its IC50 (108 μM) toward RAW264.7 cells. Loxapine at 4μM displayed the same inhibitory activity in combined with different aminoglycosides and was effective against multidrug-resistant S. Typhimurium strains. Next, the growth curve of S. Typhimurium proved that loxapine doesn’t suppress the bacteria directly, and the viability of host cells also proved that loxapine might have the ability to protect infected cells. To further investigate the complementary between loxapine and aminoglycosides, we tested the intracellular accumulation and uptake of aminoglycosides, but the results just indicate that the increase inhibition was not caused by the loxapine co treatment. Finally, we evaluate the in vivo efficacy of loxapine combined gentamicin in Salmonella-infected BALB/c mice. Surprisingly, loxapine didn't present the same effect in the in vivo test. The survival rate of combination group didn't show any significant difference compared with aminoglycoside-only group. The lack of efficacy might be due to the low serum concentration of loxapine, increasing the difficulty for loxapine to reach the antibacterial concentration in vivo.
According to these findings, loxapine possesses a unique host-targeting antibacterial effect against intracellular pathogen and would be a potential antibiotic adjuvant for the treatment of intracellular bacterial-infection. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T09:23:00Z (GMT). No. of bitstreams: 1 ntu-106-R04424019-1.pdf: 1396414 bytes, checksum: 1d1dfc356c27abe8e62f84a1cb47054a (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 致謝................................................................................................................................i
中文摘要........................................................................................................................ii Abstract....................................................................................................................... iii Contents ........................................................................................................................v 1. Introduction..............................................................................................................1 1.1 Intracellular Bacterial Infection and Its’ Problem in Clinical Treatment. ....................................................................................................2 1.2 The Model Used in This Study ─ Salmonella enterica serovar Typhimurium...............................................................................................3 1.3 Host-Targeting Agent for Intracellular Bacteria-Inhibition ...................4 1.4 The Potential of Antipsychotic Drug to Be Used as Novel Antibacterial Agent.............................................................................................................5 1.5 Specific Aim.................................................................................................6 2. Materials and Methods............................................................................................7 2.1 Bacteria Strain and Culture Condition.....................................................8 2.2 Cell Lines and Culture Condition .............................................................8 2.3 Drugs and Reagents ....................................................................................9 2.4 Cell Viability Assay .....................................................................................9 2.5 Minimum Inhibitory Concentration Assay ............................................10 2.6 Preparation of Bacteria for In vitro and In vivo tests ............................ 11 2.7 Colony Forming Assay of Intracellular S. Typhimurium Growth Analysis....................................................................................................... 11 2.8 Extracellular Growth Inhibition Assay...................................................12 2.9 Analysis of Entry of Aminoglycosides into Macrophages .....................13 2.10 In Vivo Assessment of Antibacterial Efficacy against S. Typhimurium Infection in BALB/c Mice .........................................................................15 2.11 Statistical Analysis...................................................................................16 3. Results .....................................................................................................................17 3.1 A New Host-Targeting Antibacterial Drug ─ Loxapine .....................18 3.2 Combination Treatment of Loxapine and Aminoglycosides .................18 3.3 Antibacterial Effect of Loxapine Combined with Gentamicin against Intracellular Salmonella Typhimurium...................................................19 3.4 The Effect of Loxapine on S. Typhimurium Growth and Infected-Cells .....................................................................................................................21 3.5 Suppressive Activity of Aminoglycosides and Loxapine Combination on Multidrug-resistant S. Typhimurium.................................................22 3.6 The Anti-Salmonella Typhimurium Effect of Different Aminoglycosides Combined with Loxapine..........................................................................23 3.7 The Accumulation and Uptake of Aminoglycosides Under the Combination with Loxapine .....................................................................24 3.8 The Efficacy of Loxapine and Aminoglycosides Combination in Murine Salmonellosis Model ....................................................................25 4. Discussion................................................................................................................27 4.1 The Combination of Loxapine with Aminoglycosides Showed Significant Suppressive Activity at In Vitro Test.....................................28 4.2 The Combination of Loxapine with Aminoglycosides didn’t Show Any Suppressive Efficacy on Salmonella-Infected Mice. ...............................29 4.3 The Change of the Bacterial Burden in Time Course Assay.................30 4.4 The Antibacterial Mechanism of Loxapine. ...........................................31 4.5 Conclusion. ................................................................................................33 5. References ...............................................................................................................34 6. Tables.......................................................................................................................42 Table 1. Cell cytotoxicity and bacteria inhibition of six antipsychotic drugs. .....................................................................................................................43 Table 2. MIC of four aminoglycosides against S. Typhimurium ATCC14028 .....................................................................................................................44 Table 3. The accumulation of aminoglycosides alone or combined with loxapine in macrophage. ...........................................................................45 7. Figures.....................................................................................................................46 Figure 1. Antibacterial efficacy of loxapine combined with gentamicin against intracellular Salmonella Typhimurium......................................47 Figure 2. Time-course assay of loxapine’s anti-Salmonella effect .................49 Figure 3. Effect of loxapine on Salmonella Typhimurium growth and infected-cell viability..................................................................................51 Figure 4. The bacteria suppressive efficacy of gentamicin and loxapine combination on antibiotic-resistant Salmonella Typhimurium. ............54 Figure 5. The bacteria suppressive efficacy of loxapine combined with different aminoglycosides on S. Typhimurium ATCC14028. ................56 Figure 6. Intracellular aminoglycosides accumulation in the presence of loxapine.......................................................................................................58 Figure 7. The efficacy of the combination of aminoglycosides and loxapine in the survival of Salmonella-infected mice. ................................................59 | |
| dc.language.iso | en | |
| dc.subject | 胞內抑菌 | zh_TW |
| dc.subject | 抗生素佐劑 | zh_TW |
| dc.subject | 沙門氏菌 | zh_TW |
| dc.subject | Facultative intracellular bacteria | en |
| dc.subject | antibiotic adjuvant | en |
| dc.subject | Salmonella Typhimurium | en |
| dc.title | 再利用抗精神疾病藥物Loxapine作為宿主標的性抗菌藥物對抗鼠傷寒沙門氏菌感染之效力 | zh_TW |
| dc.title | Repurposing An Antipsychotic Drug, Loxapine, As A Host-Targeting Antibacterial Agent Against Salmonella Typhimurium Infection | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蕭崇瑋(Chung-Wai Shiau),張永祺 | |
| dc.subject.keyword | 抗生素佐劑,胞內抑菌,沙門氏菌, | zh_TW |
| dc.subject.keyword | Facultative intracellular bacteria,antibiotic adjuvant,Salmonella Typhimurium, | en |
| dc.relation.page | 59 | |
| dc.identifier.doi | 10.6342/NTU201701064 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-06-23 | |
| 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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