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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM084077-04
Application #
7837747
Study Section
Special Emphasis Panel (ZRG1-GGG-T (40))
Program Officer
Jones, Warren
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$937,144
Indirect Cost
Name
University of Kansas Lawrence
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Pfannenstiel, Brandon T; Zhao, Xixi; Wortman, Jennifer et al. (2017) Revitalization of a Forward Genetic Screen Identifies Three New Regulators of Fungal Secondary Metabolism in the Genus Aspergillus. MBio 8:
Soukup, Alexandra A; Fischer, Gregory J; Luo, Jerry et al. (2017) The Aspergillus nidulans Pbp1 homolog is required for normal sexual development and secondary metabolism. Fungal Genet Biol 100:13-21
Sung, Calvin T; Chang, Shu-Lin; Entwistle, Ruth et al. (2017) Overexpression of a three-gene conidial pigment biosynthetic pathway in Aspergillus nidulans reveals the first NRPS known to acetylate tryptophan. Fungal Genet Biol 101:1-6
Oakley, C Elizabeth; Ahuja, Manmeet; Sun, Wei-Wen et al. (2017) Discovery of McrA, a master regulator of Aspergillus secondary metabolism. Mol Microbiol 103:347-365
Henke, Matthew T; Soukup, Alexandra A; Goering, Anthony W et al. (2016) New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in Aspergillus nidulans. ACS Chem Biol 11:2117-23
Yeh, Hsu-Hua; Ahuja, Manmeet; Chiang, Yi-Ming et al. (2016) Resistance Gene-Guided Genome Mining: Serial Promoter Exchanges in Aspergillus nidulans Reveal the Biosynthetic Pathway for Fellutamide B, a Proteasome Inhibitor. ACS Chem Biol 11:2275-84
van Dijk, J W A; Wang, C C C (2016) Heterologous Expression of Fungal Secondary Metabolite Pathways in the Aspergillus nidulans Host System. Methods Enzymol 575:127-42
Soukup, Alexandra A; Keller, Nancy P; Wiemann, Philipp (2016) Enhancing Nonribosomal Peptide Biosynthesis in Filamentous Fungi. Methods Mol Biol 1401:149-60
Chiang, Yi-Ming; Ahuja, Manmeet; Oakley, C Elizabeth et al. (2016) Development of Genetic Dereplication Strains in Aspergillus nidulans Results in the Discovery of Aspercryptin. Angew Chem Int Ed Engl 55:1662-5
Lin, Tzu-Shyang; Chiang, Yi-Ming; Wang, Clay C C (2016) Biosynthetic Pathway of the Reduced Polyketide Product Citreoviridin in Aspergillus terreus var. aureus Revealed by Heterologous Expression in Aspergillus nidulans. Org Lett 18:1366-9

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