Activate Silent and Cryptic Intact Fungal SM Gene Clusters through FACs for Novel Antibiotics Discovery

DESCRIPTION provided by applicant There is societal need for new therapeutic agents in our arsenal of defenses against bacterial and fungal pathogens many of which are increasingly resistant to existing antibiotics Filamentous fungi are considered promising resources for the development of novel bioactive compounds because of their great potential to produce various kinds of secondary metabolites SM however antibiotic discovery and production in fungi lags far behind bacteria This research proposal advances sciences of fungal functional genomics to activate fungal silent SM clusters by using the newly developed fungal artificial chromosomes FACs Our purpose is to discover novel antibiotics and identify the best lead candidates for clinical development Scientists at Intact Genomics Inc and the University of Wisconsin at Madison will develop utilize and combine three aspects of novel technology innovation and genomic tools to enable therapeutic agent discovery in fungi Specifically the proposed research will identify antibiotic compounds using genetically enhanced A nidulans strains in vitro BAC FAC engineering and culture conditions with epigenetic modifications and bacterial co culture The primary objectives are to activate at least of silent and or cryptic SM gene clusters FACs of A terreus for proof of concept using the above technologies and to screen these activated FACs against bacterial and fungal tester strains to discover novel antibacterial and antifungal properties Our long term goals are to develop a high through put small molecule discovery platform in fungi in order to discover novel natural products from at least silent SM pathways from completely sequenced fungal genomes Moreover we will characterize identified antimicrobial agents to determine the best lead candidates for clinical development Lead candidates will have novel chemical structures high potency against bacterial and or fungal pathogens and minimal toxicity for eukaryotic cells Each of the different technologies necessary for the proposed research has been proven effective separately therefore the combination of these different techniques has a high probability of success and also represents a significant advancement for the science of antibiotic discovery In addition the activated silent SM clusters and their metabolites produced from this research are a valuable resource that may be screened for other bioactive compounds e g with anticancer or antiviral activities in subsequent research PUBLIC HEALTH RELEVANCE The need for new therapeutic agents has reached an intensity not experienced since the commercialization of antibiotics in the s but many traditionally fruitful sources of chemistry have ceased to yield new compounds This research will develop utilize and combine three aspects of novel technology innovation and genomic tools to enable therapeutic agent discovery in the successfully engineered fungal host Aspergillus nidulans by activating and expressing fungal silent secondary metabolic pathways directly without the need to cultivate and engineer the different fungi in a laboratory This technology will access the nove small molecules produced by a great diversity of filamentous fungi many of which are unknown to science and will identify the best novel therapeutic compounds for use in treating bacterial and fungal diseases