細菌轉醣化之研究:設計及合成轉醣酶之受質與抑制劑

Abstract

過去數十年中，抗生素在治療細菌感染的疾病上扮演著重要的角色。然而相繼產生的抗藥性問題，不但在治療用藥上出現危機，也對人類的健康造成極大的威脅，因此發展新穎的抗生素便成為刻不容緩的課題。細菌的細胞壁可保護細胞避免因外界的高滲透壓而脹破，對於細菌之生存是必要的，而其細胞壁主要是由肽聚醣所構成。因此我們欲以抑制肽聚醣生合成中重要的酵素－轉醣酶之活性，作為開發新型抗生素之研究目標。 首先，我們合成出轉醣酶之天然受質－Lipid II，並將其提供於轉醣酶活性檢測系統之建立。 再者，我們以一個特殊的醣為核心骨架，模擬Lipid II進行轉醣化過程時的過渡態，作為設計轉醣酶抑制劑之概念。 我們根據molecular docking的結果，成功地合成出一些具有潛力成為轉醣酶抑制劑之化合物，並將其進行轉醣酶活性與最低抑菌濃度之檢測。篩檢結果，這些化合物，對轉醣酶並無達到預期的抑制效果且無抑菌性，我們期待在未來開發有效的轉醣酶抑制劑，並成為新一代有潛力之抗生素。

The use of antibiotics has dominated therapies for bacterial infections over the past decades. Nevertheless, the emergence of antimicrobial resistance has become a serious problem and has created a major threat to public health. It is obvious that development of new antibiotics is in an urgent need. The cell wall is essential for bacterial life because of its tolerance towards the high internal osmotic pressures. An essential constituent of bacterial cell wall is the peptidoglycan. Our approach to develop new antibiotics is to inhibit transglycosylase (TG), a specific enzyme, in peptidoglycan biosynthesis pathway. In the first place, we demonstrated the synthesis of Lipid II, the natural substrate of transglycosylase, and applied to establish transglycosylase activity assay. In the second place, we chose a specific saccharide as the core structure to mimic the transition-state of the polymerization of Lipid II during transglycosylation. Several compounds were developed as possible transglycosylase inhibitors on the basis of the molecular docking model and screened for the transglycosylase activity assay and MIC assay. Through these compounds did not show the desired TG inhibition of antibacterial activity, discovery of an efficient inhibitor of transglycosylase may promise the development of potent antibiotics in the future.