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標題: | 評估以宿主為標的之抗胞內細菌感染藥物AR-12 Evaluation of a Host-Directed Antimicrobial Drug AR-12 Against Intracellular Bacterial Infection |
作者: | Jung-Hsin Lo 羅榮新 |
指導教授: | 邱浩傑 |
關鍵字: | 胞內細菌,抗微生物製劑,合併藥物, intracellular bacteria,antimicrobial agent,drug combination, |
出版年 : | 2014 |
學位: | 碩士 |
摘要: | 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。 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. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58684 |
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顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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