Candida species represent the most frequent etiological agents of opportunistic fungal invasive
infections in an expanding spectrum of immune- and medically-compromised patients, and candidiasis now
represents the third-to-fourth most frequent nosocomial infection worldwide, carrying unacceptably high
mortality rates of 30-60%, which alarmingly have remained unchanged during the last three decades. Most
recently, Candida auris has emerged as a multi-drug resistant opportunistic fungus around the globe, including
the U.S, with a notable ability to easily spread between hospitalized patients and nursing home residents
leading to major outbreaks in healthcare settings. According to data from the Centers for Disease Control and
Prevention (CDC), 90% of C. auris strains in the U.S. have been resistant to fluconazole, 30% have been
resistant to amphotericin B, and 5% have been resistant to echinocandins. Thus, the fact that some strains of
C. auris demonstrate pan-resistance to all three major classes of clinically-used antifungals agents is
particularly concerning. Indeed, in its recently released Antibiotic Resistance Threats in the United States, the
CDC has designated C. auris as one of only 5 “Urgent Threats” requiring swift and aggressive action, since
there is a grave concern that multi- and pan-resistant C. auris isolates will spread and become prevalent, and
mostly untreatable, in the years to come. Thus, there is dire need for the development of novel therapeutics
against this emerging pathogen. To conquer this formidable challenge, we propose a highly efficient approach
by establishing a novel partnership between academia (our laboratory) and a non-for profit organization
(Medicines for Malaria Ventures, MMV) in order to perform high throughput screening (HTS) of MMV’s
chemical libraries containing 180,000 small molecule compounds to identify high value compounds with novel
antifungal activity against C. auris. Although similar approaches have had a major impact in the Parasitology
field, these MMV’s libraries have never before been screened for antifungal activity. To this end, we proposed
the following: i) perform HTS of MMV’s chemical libraries to identify high value compounds with novel
antifungal activity against C. auris, for which we will use a 384-well microtiter plate based model recently
developed in our laboratory to screen MMV’s “Hit-Generation” (140K compounds) and “Diversity” (40K
compounds) chemical libraries in order to identify inhibitors of C. auris growth; and ii) to characterize the
leading compounds by performing a battery of in vitro tests to further establish their antifungal activity and
safety/toxicity properties.