Global Activators of Fungal Natural Products

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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.