耐甲氧西林金黄色葡萄球菌（MRSA）感染已成为人类所面临的全球性挑战。借助多重诱导策略，激活微生物的“沉默基因簇”，进而挖掘其隐藏的抗MRSA活性成分，是应对当前严峻形势的重要途径。鉴于该思路，项目组围绕大戟属内生菌中的抗MRSA活性生物碱开展了前期研究：利用化学生物联合评价，从滇产大戟属中筛选出一组续随子内生菌；通过混菌共培养、表观修饰和化学胁迫等宏观操控策略，诱导其产生了两类抗MRSA活性生物碱（席夫碱和吲哚生物碱）；初步实现了席夫碱的仿生合成和结构修订。基于前期发现，本项目拟从三方面开展系统探索：继续开展大戟属内生菌的批量筛选和精选诱导发酵物的深度发掘；完成席夫碱的克级合成和抗MRSA活性评价；尝试依托异源表达系统初步解析席夫碱的生合途径。该项目的成功实施可能为研发新型抗MRSA药物提供有益的探索，亦可能为发展多重诱导策略和克级仿生合成的综合研究模式提供科学依据。

Methicilin-resistant Staphylococcus aureus (MRSA) infections have globally become a severe challenge confronting human beings. It is a powerful strategy to explore cryptic anti-MRSA natural products by activation of silent biosynthetic gene clusters in the talented strains using multiple induced approaches. Aiming at the issue of current tough situation, we have performed previous studies on anti-MRSA alkaloids from the fungal endophytes of Euphorbia species. Using the chemical and biological activity screening, we firstly filtered out a set of endophytes in the whey of Euphorbia lathyris by analyzing the fermented products of the endophytes from various Euphorbia species grown in Yunnan province. Furthermore, two new classes of active alkaloids (Schiff bases and indole alkaloids) with anti-MRSA activities, were produced by using various induced approaches, including cocultivation, chemical epigenetic manipulation, chemical elicitors, and so on. Finally, we have efficiently completed the gram-scale biomimetic synthesis and structure revision of several Schiff bases. Based on these new discoveries, we will initiate this program in three aspects. Firstly, we will continue to screen out the potential endophytes from a large amount of Euphorbia species and deeply excavate cryptic products from two groups of selected fermentations. Secondly, we may finish the gram-scale synthesis of the Schiff bases and test their anti-MRSA activities in vitro and in vivo. Finally, we will preliminarily analysis biosynthesis pathway of Schiff base by means of heterologous expression. This research may provide a useful exploration for discovering the innovative anti-MRSA agents, and developing a new comprehensive method using multiple induced approaches and gram-scale synthesis.