細菌抗藥性比例的上升已經在世界上造成嚴重的公衛問題，尋找新一代的抗生素已經是刻不容緩的問題。酵素MraY位於細胞膜上，並且被認為在細胞壁生合成中執行關鍵步驟。monophospho-MurNAc-pentapeptide在酵素的催化下將decaprenyl phosphate轉化為Lipid I並且釋放出一分子的尿苷單磷酸(UMP)。由於細胞壁相對於細胞而言是細菌獨有的結構，因此針對MraY的試劑被認為可以有效避免對人類產生毒性，因此許多文章指出以MraY酵素為目標發展之策略極具潛力。
在自然界中有許多帶有脲苷結構的核甘酸天然物在文獻中被發現可以有效抑制MraY。然而這些天然物的結構複雜性以及多重立體中心導致針對原有結構進行修改上的困難。如何簡化複雜的結構而非直接使用天然物並得到有效的MraY抑制劑在化學領域上一直是一個非常大的挑戰。
在本篇文章中，我們成功開發了不帶有多重立體中心且結構較為簡化的核心骨架以利於後續方便快速的針對潛在抑制劑進行修飾。我們利用簡單的核心骨架的衍生化進行修飾使其帶有具有電荷的側鍊。數個修飾後的化合物在酵素抑制實驗中發現可以有效抑制MraY，其中最好的化合物和天然抑制劑Tunicamycin相比，在半抑制濃度有十倍的改善。在最小抑菌濃度實驗中，針對黃金色葡萄球菌的最小抑制濃度也降為天然物的四分之一。因此這些簡化後的化合物的開發研究在未來研發新一代的抗生素中非常具有潛力。

The threat of antibiotic-resistant pathogens has become an urgent public health problem in the world. The translocase MraY, one of the essential enzymes in peptidoglycan (PGN) biosynthesis, is an integral membrane protein that catalyzes the transfer of the monophospho-MurNAc-pentapeptide moiety from Park’s nucleotide (UDP-MurNAc-pentapeptide) into the undecaprenyl (C55) phosphate to give Lipid I with concomitant release of UMP. Notably, due to no counterpart in eukaryotes, molecules targeting MarY might be less toxic toward mammals. Hence, MraY is considered as one of the promising targets for developing antibacterial agents
Several natural occurring uridine-containing nucleotides have been reported to target this translocase MraY, but the structural complexity and numerous stereo centers become a hurdle to manipulate structures of natural products directly. Indeed, how to design and synthesize new developing synthetic MraY inhibitors, not directly from natural product isolation, is a chemical challenge in this research field.
　In this work, we developed simplified building blocks without many chiral centers and convenient assemble approaches plus the proper installation of a charged moiety to our nucleotide analogs. In our MraY enzyme inhibition study, several compounds showed an interesting and promising inhibitory activity against MraY. The best one showed the 10-fold improvement in the enzyme inhibition assay, and the IC50 value is about 7 μM compared to Tunicamycin (IC50 = 79 μM), the well-known MraY inhibitor. In the further antibacterial evaluation, it showed the MIC value against S. aureu. is about 4 μg/mL compared to Tunicamycin (MIC = 16 μg/mL). These simplified structures of potent inhibitors might shed light to further develop a new generation of MraY inhibitors to tackle down antibiotic resistance issues.

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