报告2摘要 

    Although natural products have been a particularly rich source of human medicines, activity-based or chemistry-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed “genome mining” as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. Characterization of strains within five of these groups resulted in the discovery of 11 previously undescribed phosphonic acid natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products. 

However, there are two big problems to be solved for this platform. First, it is very difficult to identify and isolate this kind of compounds from Nature as a consequence of their low quantity and high hydrophilicity. Here we successfully developed an isotope labeling strategy for identifying phosphonate natural products based on our recent finding that the enzyme DhpI has broad substrate specificity and can methylate a variety of C-P natural products. Second, many of these gene clusters are silent or cryptic. Here we successfully apply a plug-and-play synthetic biology strategy to activate cryptic phosphonic acid biosynthetic gene clusters. 

报告人2简介 

   高江涛，博士生导师，福建农林大学金山学者，福建省闽江学者特聘教授。2001年毕业于中国海洋大学并获得学士学位，2005年毕业于中国科学院海洋研究所并获得硕士学位，2010年毕业于美国密西西比大学药学院并获得药学博士，博士毕业后进入美国伊利诺伊大学厄本那香槟分校从事博士后研究（导师：Prof. Wilfred van der Donk，美国文理科学院院士，HHMI研究员）。长期从事后基因组时代的微生物天然产物药物的研发，其多项相关研究成果已在Chemical Reviews, Angewandte Chemie International Edition, PNAS，Science, ACS Chemical Biology, Journal of Natural Products等国际权威杂志发表。