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標題: | 合成鐵載體staphyloferrin A 來測定與HtsA受體的專一性 Synthesis of chiral staphyloferrin A analogs to probe HtsA receptor specificity |
作者: | Tang-Feng Kuo 郭棠峰 |
指導教授: | 王宗興(Tsung-Shing Wang) |
關鍵字: | 鐵載體,複合物,天然物立體組態,結合力,點擊化學, siderophore,conjugate,natural product configuration,binding affinity,click chemistry, |
出版年 : | 2015 |
學位: | 碩士 |
摘要: | 超過半世紀以來,抗生素已有效用來治療人類與動物的微生物感染疾病。然而過度使用抗生素會使致病菌大大的增加抗藥性的頻率。因此,近年來抗藥性細菌的散佈已變成主要公共衛生的威脅。不幸的是,新穎的抗生素的發現與發展的速度卻是逐年下降。在眾多抗藥性細菌中,抗藥性金黃色葡萄球菌 (Multiple-resistant Staphylococcus aureus, MRSA) 成為最大治療上的威脅,發展新抗生素用來對抗金黃葡萄球菌是迫切的。 合成上我們鎖定細菌產生的螯合鐵分子,稱為鐵載體 (siderophore)。其功用就是在限鐵環境上抓取鐵離子以供應細菌維持生存所需。鐵離子對於細菌致病性與毒性是必須的。鐵載體進行的鐵離子獲取涉及高度調控性的主動運輸,這個過程有高度選擇性與明顯效率的特徵,金黃色葡萄球菌其中一種鐵載體 Staphyloferrin A (SA) 結構已被解出。SA與鐵離子螯合之後,會與膜蛋白HtsA受體結合後送入細菌體內,因此,藉由此特性我們設計出一種鐵載體複合物 (SA conjugates)作為具有病原菌專一性的載體用來做藥物運輸以及其他生醫相關應用。SA結構由D-鳥胺酸(D-ornithine)與兩種不同光學活性的檸檬酸(citric acid)所組成,目前化學合成僅能做到合成檸檬酸為外銷旋的SA。我們可以合成絕對光學組態的SA,藉此我們可探討不同立體組態SA類似物與HtsA的結合力是否有所差異。最後,利用點擊化學,我們能合成各種鐵載體複合物,其作為高度選擇性抗生素具有極大的潛力。 Antibiotics have been used effectively to treat bacterial infections in humans and animals for over half a century. The intensive use of antibiotics has dramatically increased the frequency of drug resistance among human pathogens. As a result, the spread of antibiotic resistant bacteria has become a major public health threat in recent years. Among these bacteria, multiple-resistant Staphylococcus aureus (MRSA) represent the biggest therapeutic threat. However, the pace of antibiotic discovery to combat these pathogens has slowed down. New antibiotics against MRSA is urgent. Siderophores are iron-chelators synthesized by bacteria to sequester iron in the iron-limiting environment. They are essential for bacterial virulence and pathogenicity. Iron acquisition by siderophores involves highly regulated active transport. This process is characterized by remarkable efficiency and microbial selectivity. Staphyloferrin A (SA) is identified as one of the siderophores in Staphylococcus aureus (S. aureus). When SA scavenges iron, the Fe(III)-SA complex formed extracellularly is transported back into the cell via the HtsABC transporter. Here, we design several SA conjugates as pathogen-specific carriers for drug delivery and other medicinal applications. SA structure is composed of D-ornithine and two citric acids having different chirality. Until now, SA can only be synthesized in racemic form. We are able to synthesize SA in absolute optical configuration. Thereby we want to know the difference of the binding affinity between SA analogs and HtsA. Ultimately, by click chemistry, we can synthesize many SA conjugates. Our SA conjugates have significant potential for development of microbe-selective antibiotics. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52250 |
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顯示於系所單位: | 化學系 |
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