2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659830摘要：具多重抗藥性細菌的盛行，已對全世界的公共衛生體系形成一個嚴重威脅。因此，發展一種創新的方式，來控制這些因抗藥細菌所造成的傳染病，已是一個迫切的需求。在先前的實驗中，我們發現了一個小分子藥物，AR-12（原做為抗癌症的藥物），可抑制巨噬細胞內的鼠傷寒桿菌和土倫病法蘭西斯氏菌的感染，卻對在液態培養基中的細菌生長沒有任何影響。目前已知這個藥物的作用，是在低微米的濃度下，藉由影響宿主細胞的重要路徑，如自體吞噬，去清除侵入細胞內的細菌。鑒於AR-12 此一獨特的抗菌活性，我們計畫利用以影像為基礎的高通量分析系統，從一個以AR-12 為分子結構基礎的化合物庫裡，去篩選出新的抗細菌藥物，並以表現型微陣列晶片、生物資訊工具和分子生物的技術，去找出在AR-12 及其衍生物的抗菌機制中，扮演重要角色的宿主基因。此外，我們也會測試AR-12 及其衍生物對於其它重要胞內細菌，如化膿性鏈球菌、耶爾辛氏腸炎菌和分枝桿菌，在細胞內和老鼠體內感染的影響。除了以AR-12為基礎的化合物庫，我們也計畫利用所建立的藥物篩選平台，從台灣藥化實驗室所合成，特有的小分子化合物庫中，去篩選具潛力的抗細菌藥物。我們預期這個研究計畫將可以開發出新型態以宿主為標地的抗細菌藥物，用於治療胞內細菌所造成的感染並能減少抗藥性的產生。<br> Abstract: The emergence and epidemic of multiple-antibiotic resistant bacteria has become a seriousthreat for public health worldwide. Thus, innovative approaches for the control of suchinfections are needed. Previously, we have identified a novel small-molecule, AR-12(originally as an anticancer agent), that inhibits intracellular Salmonella Typhimurium andFrancisella tularensis in macrophages but has no suppressive effect on bacteria in growthmedium. The agent does so through targeting important cellular pathways, includingautophagy, at low μM. In light of this unique antibacterial activity of AR-12, we propose toutilize an image-based high-content assay to identify new antibacterial agents from anAR-12 focused compound library and uncover the detail action mechanism with expressionmicroarray, bioinformatics tools and molecular biology techniques to identify host genesimportant for the anti-bacterial activity of AR-12 and its optimal derivatives. Moreover, wewill also assess the inhibitory effect of the agents on other important intracellular bacteria inmacrophages and mice, including Streptococcus pyogenes, Yesinia enterocolitica andMycobacterium. In addition to the AR-12 focused compound library, we also aim to utilizeestablished drug-screening platform to identify new anti-intracellular bacteria agent(s) fromother in-house synthesized compound libraries, especially those from medicinal chemistrylaboratories in Taiwan. We expect this project will develop novel host cells directedtherapeutic agents for the treatment of diseases caused by intracellular bacteria, and reducethe incidence of drug resistance.細胞內病原菌高通量分析抗細菌藥物Intracellular pathogenic bacteriaHigh-Content assayAntibacterial agents