SBIR-STTR Award

There is societal need for new compounds in our arsenal of defenses against fungal pathogens, many of which are increasingly resistant to existing therapeutics. Antifungal compound discovery has been forgotten or neglected (see a review publication 2021 at Research Strategy). One of the best possible sources for new antifungal compounds with potentially novel mechanisms of action is within filamentous fungi, which have the greatest diversity of microbial life. This research proposal advances the science of metagenomics, to demonstrate Aspergillus nidulans as both a heterologous host and an initial antifungal screening target, to integrate with RNA sequencing and fungal pathogen screening of fungal biosynthetic gene clusters (BGCs) and genomes, and to discover novel antifungal chemicals and identify the best lead candidates for clinical development. Scientists at Intact Genomics, and University of Wisconsin at Madison have combined four key technological breakthroughs that result in an improved paradigm for screening small molecules. The improvements in fungal artificial chromosome (FAC) tools include: 1) an improved methodology for heterologous expression of full-length BGC-FACs; 2) the FAC heterologous strains expressing antifungal compounds also showing abnormal phenotypes; 3) new action mechanisms of abnormal phenotype BGC-FACs to be uncovered by RNA deep sequencing; 4) a panel of fungal pathogens for rapid and improved screening method to identify novel antifungal compounds. This Phase I SBIR will build upon the success of previous research by screening FACs for antifungal compounds. We will characterize the antifungal agents expressed by BGC-FAC clones and FAC libraries to determine the best lead candidates for clinical development. Lead candidates will have novel chemical structures, have high potency against multiple fungal pathogens, and minimal toxicity against human red blood cell. Each of the different technologies necessary for the proposed research has been proven effective separately; therefore, the synthesis of these different methods has a high probability of success and also represents a significant advancement for the science of antifungal discovery.

Public Health Relevance Statement:
PROJECT NARRATIVE In the fight against fungal infectious diseases, we are losing ground due to the development of antifungal resistance and our inability to find replacement drugs with novel action mechanisms. The loss of life and the burden of treatment is a significant public health threat to American citizens. The proposed research unleashes a new set of tools for drug discovery that permits access to the diverse fungi for novel antifungal compounds to combat the threat of fungal pathogens.

Project Terms:
absorption; Anti-Infective Drugs; Anti-Infectives; Anti-infective Preparation; AntiInfective Drugs; AntiInfectives; Antiinfective Agents; communicable disease control agent; Anti-Infective Agents; Antifungal Drug; Therapeutic Fungicides; anti-fungal; anti-fungal agents; anti-fungal drug; antifungals; Antifungal Agents; Ascomycota; Ascomycetes; sac fungi; Aspergillus nidulans; Cells; Cell Body; Chemistry; Cloning; Communicable Diseases; Infectious Disease Pathway; Infectious Diseases; Infectious Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Epidemic; Erythrocytes; Blood erythrocyte; Erythrocytic; Marrow erythrocyte; Red Blood Cells; Red Cell; blood corpuscles; fungus; Gene Cluster; Genome; Goals; Grant; Human; Modern Man; Therapeutic immunosuppression; Anti-Rejection Therapy; Antirejection Therapy; Immunosuppressive Therapy; artificial immunosuppression; immunosuppression therapy; India; Intensive Care Units; Libraries; Metabolism; Intermediary Metabolism; Metabolic Processes; Methods; Methodology; Mucormycosis; Zygomycosis; Mycoses; Fungus Diseases; fungal infection; fungus infection; United States National Institutes of Health; NIH; National Institutes of Health; Phenotype; Probability; Public Health; Publications; Scientific Publication; Research; Research Proposals; Resources; Research Resources; Rhizopus; RNA; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; Science; Technology; Triage; Universities; Wisconsin; Work; Fungal Genome; Immunocompromised; Immunocompromised Patient; Immunosuppressed Host; immunosuppressed patient; Immunocompromised Host; Businesses; improved; Phase; Medical; Chemicals; Chemical Structure; excretion; Excretory function; Individual; Licensing; Collaborations; Therapeutic; tool; Molds; Filamentous Fungi; Life; fungicide; fungicidal; Scientist; fighting; Side; secondary infection; Source; System; interest; Services; American; cytotoxicity; Lytotoxicity; success; forgetting; microbial; Toxic effect; Toxicities; Antifungal Therapy; anti-fungal therapy; fungal infectious disease treatment; Structure; novel; new technology; novel technologies; Drug Interactions; Property; Artificial Chromosomes; Genomics; drug discovery; Fungal Drug Resistance; Antifungal Drug Resistance; Antifungal Drug Resistant; Antifungal resistant; Fungus drug resistant; anti-fungal drug resistance; anti-fungal drug resistant; anti-fungal resistance; anti-fungal resistant; antifungal resistance; fungus drug resistance; resistance to anti-fungal; resistance to antifungal; resistant to anti-fungal; resistant to antifungal; Bio-Informatics; Bioinformatics; small molecule; Length; Academia; Molecular Target; in vivo; Cancer Patient; Collection; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; pandemic disease; pandemic; pre-clinical; preclinical; deep sequencing; cost; neglect; resistant; Resistance; Functional Metagenomics; Metagenomics; chemotherapy; combat; treatment strategy; candidate identification; RNA Seq; RNA sequencing; RNAseq; transcriptomic sequencing; transcriptome sequencing; screenings; screening; naturally occurring product; Natural Products; clinical development; lead candidate; fungal pathogen; fungi pathogen; pathogenic fungus; side effect; Natural Compound; naturally occurring compound