Mining the Aspergillus nidulans Secondary Metabolome

描述（由申请人提供）：本计划项目的主要目标是使用基因组学、分子遗传学和天然产物化学的协同组合来鉴定和纯化丝状真菌构巢曲霉的潜在有用的次级代谢产物。最近发表的三种曲霉属的基因组测序结果表明，这些物种具有惊人数量的次级代谢途径，这些途径是新的和有用的天然产物的潜在来源。大多数A. nidulans的次级代谢途径目前尚不清楚，三个研究小组将共同努力，以鉴定和纯化A. nidulans。项目#1由俄亥俄州州立大学的Berl奥克利博士领导，总体PI，世卫组织将开发用于系统启动子交换和通过靶向基因替换系统破坏基因的工具。一个完整的A.将产生携带关键的非核糖体肽合成酶或聚酮化合物合成酶基因缺失的构巢菌菌株。项目#2由威斯康星州大学的Nancy Keller博士领导，他将专注于染色质突变体，以增强最低表达簇的产生并激活“沉默”簇。项目3由南加州大学的Clay Wang博士领导，他将专注于A.来自奥克利和凯勒实验室的构巢菌菌株。总之，这项多学科合作将发现构巢曲霉的新次级代谢产物，并开发可用于挖掘其他真菌物种的次级代谢组以获得有价值的天然产物的方法。 与公共卫生的相关性：这三位研究人员将使用多学科的协同方法，旨在阐明生物构巢曲霉先前未探索的次级代谢产物生物合成途径的产物。我们预计该项目将产生大量令人兴奋的新天然产物，用于测试和开发新一代化疗药物，抗菌剂和其他具有医学价值的化合物。

DESCRIPTION (provided by applicant): The primary goal of this Program Project is to use a synergistic combination of genomics, molecular genetics and natural products chemistry to identify and purify potentially useful secondary metabolites of the filamentous fungus Aspergillus nidulans. The recently published sequencing of genomes of three species of Aspergillus has revealed that these species have a surprisingly large number of secondary metabolism pathways that are potential sources of new and useful natural products. The products of most of the A. nidulans secondary metabolism pathways are currently unknown and the three research groups will work together towards the goal of identifying and purifying the product(s) of each of the secondary metabolism gene clusters in A. nidulans. Project #1 is headed by Dr. Berl Oakley at Ohio State University, the overall P.I., who will develop tools for systematic promoter exchanges and for the systematic disruption of genes through targeted gene replacements. A complete library of A. nidulans strains carrying deletions of key nonribosomal peptide synthetase or polyketide synthase genes will be created. Project #2 is headed by Dr. Nancy Keller at the University of Wisconsin, who will focus on chromatin mutants to enhance the production of minimally expressed clusters and to activate "silent" clusters. Project #3 is headed by Dr. Clay Wang at the University of Southern California, who will focus on isolation and characterization of secondary metabolites produced by A. nidulans strains from the Oakley and Keller laboratories. In summary, this multidisciplinary collaboration will discover new secondary metabolites from Aspergillus nidulans and develop methods that can be used to mine the secondary metabolomes of other species of fungi for valuable natural products. Relevance to public health: The three investigators will use a multi-disciplinary synergistic approach directed towards elucidating the products of previously unexplored secondary metabolite biosynthesis pathways of the organism Aspergillus nidulans. We expect the project to generate a large number of exciting new natural products for testing and development as a new generation of chemotherapeutics, antimicrobials and other medically valuable classes of compounds.