R33_Screening a Target-Based Repurposing Library for Activity against Fungal Pathogens and Subsequent Preclinical Development of Leading Candidates

Fungal infections constitute a major threat to an ever expanding spectrum of immune- and medically-compromised patients. The opportunistic pathogenic fungi Candida spp.. Aspergillus spp. and Cryptococcus neoformans are among the most common etiologic agents of mycoses; but infections caused by other yeasts and moulds are on the rise as advances in modern medicine prolongs lives resulting in increasingly susceptible and vulnerable patients. However. fungi have recently been referred to as the ???hidden killers/the neglected epidemic??? due to a lack of concomitant public awareness in fungal disease. There is no question that the limited arsenal of antifungal agents contributes to the unacceptably high morbidity and mortality rates associated with fungal infections. Fungi are eukaryotes. and there is a paucity of selective targets that can be exploited for antifungal drug development. As a consequence. existing antifungal agents are woefully few in number and those in clinically use are mostly restricted to three classes: polyenes. azoles and echinocandins. However. their usage is severely limited by high toxicity and the emergence of resistance. To make matters even worse. some of the most troublesome emerging fungal pathogens fall completely outside of the spectrum of activity of these current antifungals. Moreover. the antifungal pipeline in most pharmaceutical companies is mostly dry. To conquer this formidable challenge we propose a highly efficient approach consisting of first screening a repurposing library to identify high value compounds with novel antifungal activity (R21 Phase). Subsequently (R33 Phase). we will advance the development of the leading hit compounds by assessing their activity in clinically-relevant animal models of fungal infections. with an overall focus on resistant infections. Altogether the strong translational impetus associated with the proposed studies. together with the complementary expertise of the assembled team of investigators covering from basic to clinical aspects of Medically Mycology. should maximize our chances for success and allow for accelerated development of new antifungal drugs. for which there is a dire need. Our main objectives for the R21 Phase are: i) to conduct a large-scale screening of Calibr???s ReFRAME chemical library to identify high value compounds with novel antifungal activity against Candida albicans biofilms and Candida auris. an emerging pathogen and increasing nosocomial threat. ii) to confirm the antifungal activity and determine the antifungal spectrum of action of hits from primary screening. The specific aims for the R33 Phase will be: i) to characterize the in vivo activity of the leading compounds in clinically-relevant animal models of fungal infection. and ii) to further characterize the in vitro antifungal activity of the leading compounds by testing them against expanded number of clinical isolates of fungal species of interest. including geographically distinct strains and isolates that are resistant to conventional antifungal agents as well as testing their in vitro activity in combination with fluconazole. amphotericin B and micafungin as representatives of each class of current antifungals.