Project Grant R44GM154504

DISCOVERING NOVEL NATURAL PRODUCTS FROM FUNGAL SPECIES - PROJECT SUMMARY ANTIMICROBIAL RESISTANCE (AMR) IS A GLOBAL PUBLIC HEALTH CRISIS, CAUSING MORE THAN 1.2 MILLION DEATHS ANNUALLY AND THREATENING TO REACH 10 MILLION PER YEAR BY 2050 WITHOUT NEW THERAPIES. INFECTIONS SUCH AS PNEUMONIA, TUBERCULOSIS, BLOODSTREAM INFECTIONS, AND GONORRHEA ARE INCREASINGLY RESISTANT TO EXISTING MEDICINES, UNDERSCORING THE URGENT NEED FOR NOVEL ANTIMICROBIALS. NEARLY ALL ANTIBIOTICS IN USE TODAY ARE DERIVED FROM MICROBIAL NATURAL PRODUCTS. HOWEVER, THE PACE OF DISCOVERY HAS SLOWED, LARGELY DUE TO REDISCOVERY OF KNOWN COMPOUNDS AND LIMITATIONS OF BIOACTIVITY-FIRST SCREENING METHODS, WHICH CAPTURE ONLY THE MOST ABUNDANT METABOLITES. ADVANCES IN GENOME SEQUENCING HAVE REVEALED MILLIONS OF BIOSYNTHETIC GENE CLUSTERS (BGCS) ENCODING THE POTENTIAL TO PRODUCE DIVERSE NATURAL PRODUCTS. YET, CURRENT COMPUTATIONAL METHODS CANNOT ACCURATELY PREDICT ENZYME FUNCTION OR FINAL MOLECULAR STRUCTURES, LEAVING THE VAST MAJORITY OF THIS BIOSYNTHETIC POTENTIAL UNTAPPED. CHEMIA BIOSCIENCES IS DEVELOPING A COMPUTATIONAL PLATFORM THAT INTEGRATES GENOME MINING WITH HIGH- THROUGHPUT MASS SPECTROMETRY TO DIRECTLY CONNECT BGCS FROM FUNGAL SPECIES TO THEIR MOLECULAR PRODUCTS. BUILDING ON PRIOR WORK IN METABOLOMICS AND MASS SPECTROMETRY-BASED DISCOVERY, THIS PROJECT WILL EXTEND THESE APPROACHES TO FUNGAL NATURAL PRODUCTS-A CLINICALLY IMPORTANT CLASS OF MOLECULES THAT INCLUDES PENICILLIN, ECHINOCANDINS, PACLITAXEL, CYCLOSPORIN, AND STATINS. THE PROPOSED RESEARCH WILL CREATE METHODS TO SYSTEMATICALLY IDENTIFY NOVEL FUNGAL METABOLITES WITH POTENTIAL THERAPEUTIC APPLICATIONS. THE RESULTING SOFTWARE WILL BE DEPLOYED AS A CLOUD-BASED SERVICE, ENABLING WIDESPREAD USE BY ACADEMIC, INDUSTRIAL, AND GOVERNMENT PARTNERS. BY EXPANDING THE ACCESSIBLE NATURAL PRODUCT SPACE, THIS WORK WILL HELP REPLENISH THE ANTIMICROBIAL PIPELINE AND ACCELERATE THE DEVELOPMENT OF URGENTLY NEEDED MEDICINES TO COMBAT RESISTANT PATHOGENS AND PROTECT PUBLIC HEALTH.