Infectious disease is the second leading cause of death worldwide. The increasing number of drug resistant microbes exacerbates this health problem, a problem that is recognized by the World Health Association as a major public concern. Antimicrobial discovery began with the fortuitous discovery of penicillin production by the fungus Penicillium and, soon after, many more natural products - most often bacterially derived - were identified and implemented in disease treatment. Despite an understanding that fungi produce an endless source of novel natural products, the use of fungi to mine antimicrobials was largely scrapped due to the seemingly inaccessible nature of metabolite production in these organisms. Here we demonstrate that immense advances in genomic knowledge of fungal secondary metabolite production now, once again, opens the door to drug mining from fungi. Using the sequenced model ascomycete Aspergillus nidulans, we propose three aims: 1. To activate global secondary metabolite regulators able to genetically manipulate the fungus into prime metabolite production. 2. To develop generic tools for increased secondary metabolite production in fungi. 3. To transition the newly identified compounds in aims 1 and 2 to bioassays of major groups of fungal and bacterial pathogens. This work will provide development of new compounds against major groups of infectious microbes that should ultimately lead to applicable new antimicrobials to increase the health of the US and worldwide public.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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University of Kansas Lawrence
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Dohn Jr, James W; Grubbs, Alexander W; Oakley, C Elizabeth et al. (2018) New multi-marker strains and complementing genes for Aspergillus nidulans molecular biology. Fungal Genet Biol 111:1-6
van Dijk, Johannes W A; Wang, Clay C C (2018) Expanding the Chemical Space of Nonribosomal Peptide Synthetase-like Enzymes by Domain and Tailoring Enzyme Recombination. Org Lett 20:5082-5085
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:
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
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
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
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
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

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