PROJECT SUMMARY Fungal infections impact hundreds of millions of people and kill >1.5 million individuals annually. The recent emergence of resistance against all three major classes of antifungals in pathogens such as Candida auris presents a grave threat to human health. Indeed, with mortality rates ~60%, C. auris is now classified as a “superbug” by the Centers for Disease Control (CDC). This program will address this therapeutic need via the discovery of small molecules that inhibit novel Cu-only superoxide dismutases (SODs). During infection, the host can produce a toxic burst of superoxide (O2-•) to attack microbes. However, fungal pathogens produce extracellular SODs that disproportionate O2-•. The co-I (Culotta, JHU) has discovered a new class of extracellular, Cu-dependent SOD metalloenzymes that are unique to fungi, distinct from human SODs, and essential for the virulence of widespread fungal pathogens. These ‘Cu-only’ SODs are highly conserved in fungal kingdom and our data suggests they are a promising, untapped antifungal targets. This exploratory effort (R21) will identify inhibitors of fungal Cu-only SODs using an innovative approach to metalloenzyme inhibitor discovery developed in the laboratory of the PI (Cohen, UCSD). This approach utilizes metalloenzyme fragment-based drug discovery (mFBDD) and does not involve removal of the metal ion from the enzyme active site. The laboratory of the PI has a strong track record of identifying first- or best-in-class inhibitors of metalloenzymes by using mFBDD. In this effort, we will focus on Cu-only SOD5 from the fungal pathogen C. albicans, followed by validation of our approach with Cu-only SOD4 from drug resistant C. auris. Promising MBP hits will be developed in a hit-to-lead effort into inhibitors that will be screened for activity against fungal infections in vitro and in vivo. Ultimately, this program will discover first-in-class inhibitors of fungal Cu-only SODs and demonstrate their utility as a novel therapeutic target against these life-threatening infections.

PROJECT NARRATIVE Fungal disease kills more than 1.5 million people annually. There is a dire need for new therapeutic interventions to treat these challenging infections. The proposed research effort will develop and evaluate inhibitors of newly discovered, Cu-only superoxide dismutase (SOD) enzymes found exclusively in fungi that could serve as a novel target for therapeutic intervention.