利用磷酸基甘油酸辛基醚之脂類衍生物研究對細菌轉醣酶的抑制性

Using Phosphoglycerate Octyl Ether-Lipid Derivatives to Study the Inhibition of Bacterial Transglycosylases

蔡宛蓁(Wan-Chen Tsai)

指導教授 ： 方俊民

國立臺灣大學/理學院/化學研究所/碩士(2014年)

https://doi.org/10.6342/NTU.2014.01717

摘要

在現在這個時代，抗生素是人類用來對抗細菌感染的重要利器。然而，濫用抗生素的情況下，導致許多具抗藥性的菌種相繼產生，開發新穎的抗生素成為刻不容緩的目標。細菌細胞壁的主要成分為肽聚糖，其主要功用為維持細菌細胞形狀來抵抗外界滲透壓差，對細菌之生存是相當重要的。細菌細胞壁的生合成路徑主要是透過轉胜肽酶和轉醣酶催化下所進行，由於轉醣酶裸露在細胞膜外側，藥物不需進入細胞膜內即可對酵素進行抑制，因此被科學家們認為以此為目標開發新型的抗生素是相當具有潛力的。
我們所設計之轉醣酶抑制劑，主要概念是以模擬lipid II為單體，在轉醣化過程中所形成的過渡態之電荷和結構，搭配天然轉醣酶抑制劑—moenomycin作為結構的參考，設計出一系列具有潛力的轉醣酶抑制劑。我們以moenomycin脂質區特徵基團作為基礎骨架，以短鏈(C8)之phosphoglycerate衍生物來模擬lipid II的雙磷酸脂質鏈，透過適當長度的連接鏈，連接模擬lipid II多醣部分骨架之芳香環結構。 合成出所設計之一系列轉醣酶抑制劑之後，我們透過轉醣酶活性分析及最低抑菌濃度檢測來驗證所設計之化合物是否具抑菌能力。在這幾個合成之phosphoglycerate衍生物中，苯環上帶有能產生氫鍵的官能基之化合物，對金黃色葡萄球菌的最低抑菌濃度為100 μM，但是在相同濃度下對轉醣酶卻不具有抑制性。綜合所有本實驗室所設計之轉醣酶抑制劑，我們認為保留磷酸鹽（phosphate）結構是必要的，之後再利用還原胺化方式引入能產生氫鍵作用力的取代基（如OH基）之苯環結構，同時保留苯環與氨基酸殘基之作用力，還能產生額外氫鍵吸引力，期望能提抑制劑之抑制活性，開發出更有潛力的轉醣酶抑制劑。

關鍵字

轉醣酶抑制劑

並列摘要

In this day and age, antibiotics are used to treat people for bacterial infections. However, abuse of antibiotics also leads to the appearance of multi-drug resistant bacteria. There is an urgent need to develop new agents that are active against multi-drug resistant bacteria. The main constituent of bacteria cell wall is peptidoglycan, which is responsible for a defined cell shape to allow bacteria to live in a variable internal osmotic environment. Transpeptidase (TPase) and transglycosylase (TGase) are two major enzymes which can catalyze the synthesis of bacteria cell wall. TGase is located on the external surface of bacterical cell membrane, so that it is unnecessary for inhibitors to enter cytoplasm. We consider TGase as a promising antibiotic target due to its essential function and ready accessibility.
We have designed and synthesized some potential transglycosylase inhibitors with an aryl moiety bearing several hydrogen-bonding groups to mimic the saccharide part of lipid II, the nature substrate of TGase. In addition, a long chain phosphoglycerate was used to mimic the long chain pyrophosphate part of lipid II. These inhibitors are designed to block the process of transglycosylation by mimicking the transition state in lipid II polymerization. Some potential transglycosylase inhibitors were synthesized and subjected to the HPLC-based TGase fluorescence assay and MIC assay. Among these derivatives of phosphoglycerate with the aryl moiety bearing hydrogen-bonding groups showed the best MIC value of 100 μM against Staphylococcus aureus. However, it showed no inhibition against TGase at same concentration. Among all of the transglycosylase inhibitors designed in our laboratory, we considered that it is necessary to retain phosphate structure and introduce benzene structure bearing hydrogen-bonding groups (e.g. OH). We hope that through the interaction between benzene ring and amide side chain and further hydrogen bonding might improve the inhibitory activity to act as efficient TGase inhibitors.

並列關鍵字

Inhibition of Bacterial Transglycosylases

參考文獻

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