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.

Relevance There are no effective therapies for the emerging resistant fungal pathogens that are becoming an increasing threat to the public health. The goals of this project are to further develop a drug from a promising new antifungal class to address this unmet clinical need for growing immunocompromised patient populations.