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Title: | 設計與合成磷酸基甘油酸衍生物來抑制細菌轉醣酶 Design and Synthesis of Phosphoglycerate Derivatives for inhibition of Bacterial Transglycosylase |
Authors: | Huei-Ru Wu 吳蕙如 |
Advisor: | 方俊民(Jim-Min Fang) |
Keyword: | 轉醣?,抑制劑,抗生素, transglycosylase,moenomycin,antibiotics, |
Publication Year : | 2016 |
Degree: | 碩士 |
Abstract: | 抗生素的濫用造成許多具有多重抗藥性的細菌大量繁衍,嚴重威脅到人類的存亡,發展出新穎且有效的抗生素便有著刻不容緩的需求。細菌的細胞壁是由肽聚醣所組成,其生合成涉及了一個重要的酵素”轉醣酶”的催化,轉醣酶裸露在細胞膜外側,因此藥物不需經由通過細胞膜便可直接抵達酵素進行抑制,故以轉醣酶為目標而開發的新型抗生素是極具吸引力的。
我們設計並合成出一系列具有潛力的轉醣酶抑制劑,利用帶有不同取代基的聯苯結構模擬單體lipid II在進行轉醣化過程中所形成過渡態之電荷與結構,並搭配轉醣酶的天然抑制劑moenomycin的特徵基團”磷酸甘油酸”為基礎架構,利用較短碳鏈的磷酸甘油酸衍生物來改善抑制劑的生體可用率,再以胺基或醯胺基連接鏈結合上述兩個片段。 成功合出一系列具有潛力的轉醣酶抑制劑後,我們透過高效液相層析‒轉醣酶活性分析法及最低抑菌濃度檢測來確認所合成之抑制劑是否具有良好的抑菌效果。在一系列磷酸甘油酸衍生物中,聯苯上帶有能產生氫鍵官能基並具有胺基連接鏈的化合物,其轉醣酶活性檢測具有最佳抑制性在100 uM有76%抑制性,但因為活體實驗較酵素實驗複雜,因此該化合物的最低抑菌濃度大於100 uM。綜合本文實驗結果,我們認為帶有能產生氫鍵官能基的聯苯結構及能產生正價性質之胺基連接鏈是相當重要的,因此在未來化合物的結構衍生修飾上,我們將保有這些特性,並藉由更改磷酸甘油酸上的脂質鏈來增加化合物及酵素之間的作用力,期望能開發出具有更佳抑制效果的轉醣酶抑制劑。 The abuse of antibiotics results in dramatic increase of multi-drug resistant bacteria which become a serious threat to human health. Developing novel and effective antibiotics against resistant bacteria is undoubtedly required. Bacteria cell wall is constituted by peptidoglycan which is formed involving the catalysis by an important enzyme transglycosylase (TGase). TGase is located on the external of cell membrane, so inhibitors can reach TGase without entering cytoplasm. Therefore, TGase becomes an attractive target for development of new antibiotics. We designed and synthesized a series of potential TGase inhibitors that contain a biphenyl moiety with different substituents to mimic the oxonium transition state during the lipid II transglycosylation. A phosphoglycerate moiety which is a characteristic group of moenomycin bearing a curtailed aliphatic chain is incorporated into the designed inhibitors to improve the bioavailability. The two above-mentioned moieties are connected by amide or amine linker. Some potential transglycosylase (TGase) inhibitors were synthesized and subjected to the HPLC-based TGase fluorescence assay and MIC assay. Among all the synthesized phosphoglycerate derivatives, a compound bearing an amine linkage and a biphenyl moiety with four hydroxyl substituents showed the best TGase inhibitory activity of 76% at 100 uM. The cell experiment is usually more complicated than the enzymatic assay due to more controlling factors. Hence, this compound was inactive to bacteria, showing MIC values above 100 uM. Among all of the transglycosylase inhibitors designed here, we considered that the phosphoglyceric acid, amine linkage and multiple substituted biphenyl are important moieties to provide the desired interactions with the active site of TGase. To further explore more effective TGase inhibitors, we will keep the important properties of current compounds but elongate the lipid substituent to improve the interaction with TGase. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78200 |
DOI: | 10.6342/NTU201601063 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 化學系 |
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ntu-105-R03223122-1.pdf Restricted Access | 11.28 MB | Adobe PDF |
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