# Inhibitors of Cu-only Superoxide Dismutases as Novel Antifungals

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $202,166

## Abstract

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.

## Key facts

- **NIH application ID:** 10888670
- **Project number:** 1R21AI180103-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SETH M COHEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $202,166
- **Award type:** 1
- **Project period:** 2024-01-19 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888670

## Citation

> US National Institutes of Health, RePORTER application 10888670, Inhibitors of Cu-only Superoxide Dismutases as Novel Antifungals (1R21AI180103-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10888670. Licensed CC0.

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