R01AI167883

Symbiotic-Based Discovery of Turbinmicin, a Safe and Selective Antifungal Against Resistant Fungi

New antifungal drugs are needed to address the emergence of pan-drug resistant fungal pathogens that threaten a growing immunocompromised patient population. Underscoring this urgency is the recent global spread of Candida auris, which is resistant to all three of the available antifungal classes.

Natural products from bacteria have served as an important source of anti-infectives, including antifungals. We leveraged new sources of bacteria harvested from marine invertebrate microbiomes to generate natural product screening libraries and identified Turbinmicin, a novel antifungal targeting multidrug resistant (MDR) fungal pathogens.

Turbinmicin displays potent in vitro and in vivo efficacy toward multiple MDR-fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting the vesicular trafficking pathway. We subsequently synthesized Turbinmicin analogs to modulate the pharmaceutical properties including solubility. Based on our promising results, our premise is that Turbinmicin analogs represent the next generation of safe and effective antifungal targeting drug resistant fungal infections.

In this project, the Wisconsin Drug Discovery and Development Center will use lead optimization to develop Turbinmicin, a novel natural product representative from a new class of broad-spectrum and non-toxic antifungals. The aims are focused on efficacy (Specific Aim 1), safety (Specific Aim 2), and production/formulation (Specific Aim 3). We divide each of the three aims into two sequential stages. Stage 1 will identify the most promising lead analog based upon efficacy, safety, and solubility screens. Stage 2 will delineate IND-enabling PK/PD efficacy and safety in established murine models and rat models, respectively.

Impact: As there are no effective therapies for emerging pan-drug resistant fungal pathogens, our work fills a critical unmet need. Our studies will provide several IND-enabling datasets for clinical development of a new class of antifungal targeting high threat drug-resistant fungi. The investigations use complementary, cutting-edge technologies to test the efficacy and safety of the Turbinmicin compound series, and optimize drug production. The research will be performed in outstanding environments by a cohesive group of PIs and industry partners, with complementary expertise in preclinical and clinical antimicrobial pharmacology and natural product chemistry.

University Of Wisconsin System

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Madison, Wisconsin 53715 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 288% from $777,498 to $3,015,316.