耐药性革兰氏阴性（G-）病原菌已列为当前重点病原体，抗生素的枯竭正使其逐步威胁全球公共健康。煤矿区是一个极酸、极盐、高重金属含量等多极端复杂环境区域，孕育了多种特殊的真菌，是新药发现的重要资源。但由于实验室培养条件无法还原极端环境，外源激活沉默型次生代谢产物合成基因簇显得尤为重要。前期从贵州省兴仁晚二叠纪煤矿区土壤中分离筛选获得2株具有抗多药耐药性大肠杆菌的真菌，经对其中一株代谢物的化学成分研究，发现其新型异香豆素类化合物在联合抗耐大肠杆菌实验中使头孢曲松钠的MIC从1024μg/mL降到256μg/mL，同时该菌株在外源化学诱导下能代谢合成结构多样性的化学分子。因此本项目拟在此基础上，广泛采集该特境下的真菌，以4种耐G-菌为指示菌，通过化学表观遗传调控，结合生物自显影及液质分析和现代分离、鉴定手段，以期获得具有抗耐G-病原菌的新型化合物，并利用分子生物学技术阐明1-2个化合物的作用机制。

Drug-resistant Gram-negative (G-) pathogens have been reported as current key pathogens which are gradually threatening global public health due to the depletion of antibiotics. The coal mine area is a complex environment area with extreme acidity, rich salt, high heavy metal content, etc., breeding a variety of special fungi. However, for the inability of restoring extreme environments for fungi culture condition in laboratory, it is particularly important to exogenously activate secondary metabolites silent synthesis gene clusters. In the preliminary experiment, two strains of fungi with anti-multi-drug resistant Escherichia coli were isolated from the soil of the Late Permian coal mine in Xingren, Guizhou Province. The chemical constituents from metabolites of one strain were studied, and a new isocoumarin revealed potential decreasing the amount of Cephalosporin sodium (1/4MIC) in the combination antibacterial test. And the strain can produce diverse metabolites under the induction of exogenous chemical molecule. Therefore, the project is to collect the fungi from this special environment with four drug-resistant G- bacteria as indicator, to obtain new compounds with anti-drug resistance G- pathogens under the chemical epigenetic regulation of strains, combining with bioautography and LC-MS analysis as well as modern separation and identification, and to explain the mechanism of 1 to 2 compounds by molecular biology techniques.