Project Grant R43AI174320

ANTIFUNGAL DISCOVERY FROM PREVIOUSLY UNCULTIVATED BACTERIA - ABSTRACT CANDIDA AURIS IS A MULTIDRUG-RESISTANT YEAST THAT CAN CAUSE INVASIVE INFECTION AND DEATH. IT SPREADS EASILY BETWEEN HOSPITALIZED PATIENTS AND NURSING HOME RESIDENTS. C. AURIS IS ESPECIALLY HAZARDOUS TO IMMUNOSUPPRESSED PATIENTS AND THOSE HOSPITALIZED WITH COVID-19. PARTICULARLY CONCERNING, SOME STRAINS OF C. AURIS ARE RESISTANT TO ALL THREE MAJOR CLASSES OF ANTIFUNGAL DRUGS. AS A RESULT, THIS DEADLY PATHOGEN HAS BEEN CLASSIFIED AS AN URGENT THREAT BY THE CENTERS FOR DISEASE CONTROL (CDC), AND NEW ANTIFUNGAL DRUGS ARE DESPERATELY NEEDED. MOST ANTIFUNGAL DRUGS ARE DERIVED FROM NATURAL COMPOUNDS PRODUCED BY ENVIRONMENTAL MICROORGANISMS. HOWEVER, SCREENING FOR ANTIFUNGALS FROM THIS SOURCE HAS FALLEN INTO DISFAVOR, AS THE READILY CULTURABLE MICROORGANISMS HAVE BEEN OVERMINED. HOWEVER, 99% OF ENVIRONMENTAL MICROORGANISMS HAVE NEVER BEEN SCREENED BECAUSE THEY WILL NOT GROW UNDER NORMAL LABORATORY CONDITIONS. TO ADDRESS THIS PROBLEM, WE USED OUR ICHIP CULTURING TECHNOLOGY TO ASSEMBLE A LARGE COLLECTION OF PREVIOUSLY UNCULTURED MICROORGANISMS. THE ICHIP ENABLES MICROORGANISMS TO GROW IN THEIR NATURAL ENVIRONMENT (E.G., SOILS), GIVING THEM ACCESS TO ESSENTIAL GROWTH FACTORS. AS A RESULT, WE SCREEN MICROORGANISMS THAT ARE INACCESSIBLE TO OTHER DRUG DISCOVERY PROGRAMS. WE HAVE USED THE ICHIP TECHNOLOGY TO DISCOVER SEVERAL NEW ANTIBACTERIAL COMPOUNDS SUCH AS TEIXOBACTIN, WHICH IS CURRENTLY IN IND-ENABLING STUDIES TO TREAT DRUG-RESISTANT BACTERIAL INFECTIONS. IN THIS PROJECT WE WILL SCREEN OUR UNIQUE MICROBE COLLECTION FOR COMPOUNDS THAT KILL C. AURIS. IN PRELIMINARY STUDIES, WE SCREENED A SMALL NUMBER OF OUR ICHIP ISOLATES (3,000) AGAINST C. AURIS. FROM THIS LIMITED SCREENING, WE HAVE ALREADY FOUND FIVE POTENTIALLY NOVEL ANTIFUNGALS, WHICH WE WILL PURSUE IN THIS PROJECT. IN ADDITION, WE WILL SCREEN A MUCH LARGER NUMBER OF OUR ISOLATES (30,000) TO OBTAIN ADDITIONAL PROMISING COMPOUNDS. CRUDE EXTRACTS WILL FIRST BE PRODUCED FROM FERMENTATIONS AND SCREENED AGAINST C. AURIS. THE COMPOUNDS PRODUCING THE ANTIFUNGAL ACTIVITY WILL THEN BE ISOLATED FROM THE EXTRACTS TO DETERMINE THEIR CHEMICAL NOVELTY, POTENCY AGAINST OTHER IMPORTANT FUNGI (INCLUDING DRUG-RESISTANT STRAINS), CYTOTOXICITY, AND FREQUENCY OF RESISTANCE. PROMISING COMPOUNDS WILL THEN BE TESTED IN A MOUSE EFFICACY MODEL OF FUNGAL INFECTION (DISSEMINATED CANDIDIASIS). COMPOUNDS THAT SHOW GOOD ANIMAL EFFICACY WILL BE CONSIDERED LEAD COMPOUNDS AND THEIR FULL CHEMICAL STRUCTURE WILL BE ELUCIDATED. OUR GOAL AT THE END OF THIS PROJECT IS TO DISCOVER 1-2 NOVEL LEAD COMPOUNDS FOR PRECLINICAL DEVELOPMENT TO COMBAT C. AURIS AND POTENTIALLY OTHER FUNGAL INFECTIONS.