Gene activation strategies to unlock fungal secondary metabolism and its function

许多丝状真菌产生的次级代谢产物被认为在物种内和物种间的交流，资源竞争或共生伙伴的防御中具有决定性作用。此外，它们中的大多数具有独特的化学结构，并且通常具有强大的生物活性，因此对药物发现具有特殊的兴趣。除了这些代谢物的重要性，据估计，只有一小部分的真菌次生代谢物已被确定，和一个小得多的分数生态功能进行了充分的研究。因此，拟议的研究目标是基因激活策略，以解锁生物合成基因簇，这些基因簇在标准实验室条件下是沉默的，并获得子囊菌的新次级代谢产物。为此，将应用不同的培养条件和通过组蛋白甲基化抑制进行表观遗传学操作。代谢组学将满足转录组学，以快速鉴定新表达的代谢产物，并整合相应的生物合成基因簇的基因表达。由于在选定的四种真菌基因组中发现新的化学实体具有巨大的潜力，因此目标是确定新代谢物的绝对构型，并通过利用一组专注于抗微生物活性的测定来检查其生物学功能。

Many filamentous fungi produce secondary metabolites that are believed to have decisive roles in intra- and inter-species communication, competition for resources, or defense of a symbiotic partner. Moreover, most of them bear unique chemical structures and are often privileged with potent bioactivities and therefore are of exceptional interest for drug discovery. Besides the importance of these metabolites, it is estimated that only a small fraction of fungal secondary metabolites has been identified, and for a much smaller fraction ecological functions are well-studied. Thus, the proposed research targets gene activation strategies in order to unlock biosynthetic gene clusters, which are silent under standard laboratory conditions and to access new secondary metabolites of Ascomycetes. For this purpose, varying culture conditions and epigenetic manipulation via histone methylation inhibition will be applied. Metabolomics will meet transcriptomics to rapidly identify newly expressed metabolites and to integrate corresponding gene expression of respective biosynthetic gene clusters. Since there is a tremendous potential to discover new chemical entities within selected four fungal genomes, the goal is to determine the absolute configurations of novel metabolites and to examine their biological function by leveraging a panel of assays with a focus on antimicrobial activity.