Discovering novel antifungal agents via multi-species profiling of a structurally and stereochemically diverse; well-validated compound library

PROJECT SUMMARY Invasive fungal infections are an increasing public health threat and current antifungaltherapy is extremely difficult due to the emergence of multi-drug or totally resistant strains as wellas new pathogenic species. Because the biology of these organisms is unique compared to othercommon microbial pathogens, the arsenal of drugs to treat invasive fungal infections frequentlyexhibits limited efficacy and toxicity. In this program, we propose to conduct a series of screensusing a compound library that has shown great success in providing lead compounds andpreclinical candidates for oncology and metabolic diseases, bacterial infections (pan-Gramnegative bacteria, Clostridium difficile-specific, and Mycobacterium tuberculosis), and parasiticdiseases (Trypanosoma cruzi and Plasmodium falciparum). This library, assembled usingDiversity-Oriented Synthesis (DOS) principles, contains a unique collection of chemical structuresthat possess enhanced topological and stereochemical diversity, resulting in three-dimensionalcharacteristics not commonly represented in standard commercial libraries for high-throughputscreening. We have assembled a unique multi-disciplinary team with complementary expertise inscreening, chemical synthesis, fungal pathogenesis, in vitro and in vivo fungal models of disease,and the clinical treatment of invasive fungal infections. Using a miniaturized primary screenagainst four different clinically-relevant fungal pathogens (Candida albicans, Candida glabrata,Candida auris, Cryptococcus neoformans) and subsequently profiling hits against a wide rangeof yeasts, invasive molds (including Aspergillus fumigatus), and drug-resistant isolates will allowrapid and cost-effective generation of abundant activity profile data to prioritize compound seriesdemonstrating either species-specific or broad-spectrum antifungal activities via novelmechanisms of action. Molecular targets will be identified via chemical genomic approachesenabling integration of biochemical and structural biology approaches in the compoundoptimization workflow. Due to our extensive experience in advancing DOS library hits to validatedprobes and preclinical candidates, we are able to rapidly optimize compound series for potency,physicochemical properties, and metabolic stability to deliver leads suitable for profiling in in vivoinfection animal models. Our goal for this 5-year project is to identify, optimize, and validate 1 to2 novel antifungal therapeutic leads for clinical development.