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.
Public Health Relevance Statement: NARRATIVE The fungal pathogen Candida auris is a major public health concern, particularly in healthcare facilities and nursing homes. The focus of this project is to screen our unique microbial culture collection for new drugs to combat C. auris.
Project Terms: AmB; AmBisome; Amphocil; Amphotec; Amphotercin B; Fungizone; Mysteclin-F; Amphotericin B; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antibiotics; Antifungal Drug; Therapeutic Fungicides; anti-fungal; anti-fungal agents; anti-fungal drug; antifungals; Antifungal Agents; Antitubercular Agents; Tuberculostatic Agents; anti-TB; anti-tuberculosis; antiTB; antituberculosis; Bacteria; Bacterial Infections; bacteria infection; bacterial disease; Biological Assay; Assay; Bioassay; Biologic Assays; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Centers for Disease Control and Prevention (U.S.); Centers for Disease Control; Centers for Disease Control and Prevention; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Classification; Systematics; Cessation of life; Death; Droughts; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Environment; Fermentation; Fractionation; Chemical Fractionation; FRACN; Fractionation Radiotherapy; fungus; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Health care facility; Health Facilities; Healthcare Facility; care facilities; Hospitalization; Hospital Admission; Hospitals; In Vitro; Infection; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; mortality; Mus; Mice; Mice Mammals; Murine; Mycoses; Fungus Diseases; fungal infection; fungus infection; Natural Resources; Nursing Homes; nursing home; Nystatin; Nystex; mycostatin; Patients; Drug Kinetics; Pharmacokinetics; Phenotype; Production; Public Health; Safety; Soil; Staphylococcus aureus; S aureus; S. aureus; Staph aureus; Technology; Testing; Yeasts; Immunocompromised; Immunocompromised Patient; Immunosuppressed Host; immunosuppressed patient; Immunocompromised Host; falls; Disseminated candidosis; Systemic candida; Systemic candida infections; Systemic candidiasis; Disseminated candidiasis; cytotoxicity test; Acute; Clinical; Phase; Chemicals; Chemical Structure; Data Bases; data base; Databases; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; analog; Antibacterial Agents; anti-bacterial; antibacterial; Anti-Bacterial Agents; fluid; liquid; Liquid substance; Reporter; Bioreactors; microbioreactor; programs; fungicide; fungicidal; milligram; microorganism; Source; cytotoxicity; Lytotoxicity; mutant; microbial; Structure; novel; Categories; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Modeling; drug discovery; Skin; Complex Extracts; complex extract; Crude Extracts; Address; Dose; Mammalian Cell; Qualifying; in vivo; Collection; Validation; validations; Development; developmental; scale up; pathogen; resistant; Resistance; Microbe; preclinical research; pre-clinical research; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; combat; resistance strain; resistant strain; animal efficacy; screenings; screening; resistance frequency; Growth Agents; Growth Substances; Proteins Growth Factors; Growth Factor; efficacy study; pre-clinical development; preclinical development; screening program; novel lead compound; in vivo testing; in vivo evaluation; fungal pathogen; fungi pathogen; pathogenic fungus; C auris; C. auris; Candida auris; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019; coronavirus disease-19; coronavirus infectious disease-19; COVID-19; minimal inhibitory concentration; novel antibiotic class; new antibiotic class; new antibiotic type; Natural Compound; naturally occurring compound; secondary metabolite
