# HTS with Aspergillus fumigatus for novel, mold-active antifungals

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2024 · $233,250

## Abstract

PROJECT SUMMARY
 Molds cause devastating infections in diverse patient populations worldwide. The most life-threatening of
these diseases are invasive mold infections (IMIs) which primarily affect immune compromised individuals
including those undergoing chemotherapy, long term steroid treatment, and hemopoietic or solid organ transplant
patients. IMIs can be caused by a handful of environmental molds but the most common species is Aspergillus
fumigatus. Currently, there are three classes of antifungals used to treat IMIs; however, despite available
treatments, mortality rates remain unacceptably high, typically ~50% but reaching 80-100% for some mold
species and patient cohorts. One contributing factor to the high mortality rates is intrinsic resistance of some
mold species to some or all clinical antifungals. In addition, acquired antifungal resistance, particularly among A.
fumigatus isolates, is becoming a clinical problem worldwide.
 In the drug development space, antifungal drug screens often focus on yeast species. This is due in part
to the technical ease of handling these organisms in high-throughput settings. Yeast growth is tightly correlated
to optical density, facilitating large-format growth-based screens. In contrast, molds grow as filaments which
create a heterogenous culture of tangled cells whose optical density is not well correlated to biomass.
Additionally, the inability to handle these cultures with automated liquid handling devices creates additional
challenges in high throughput settings. However, the high mortality rates and limited activity of clinical antifungal
against molds warrants more focus on these organisms in antifungal drug screening.
 To address the need for mold-active antifungals, we developed and validated a high-throughput
compatible screening assay to screen directly with A. fumigatus. This luciferase-based assay measures the
release of the cytosolic enzyme, adenylate kinase (AK), as a readout for fungal cell lysis. Uniquely, when used
with A. fumigatus this assay can also detect compounds that inhibit germination through the suppression of
background AK release that occurs during normal germination and vegetative growth. Here, we propose a high-
throughput screen of a large library of synthetic, drug-like molecules for novel scaffolds with anti-mold activity
using our AK screening platform. Pilot large-format screens have already identified candidate molecules for
further development; thus, based on the scale and diversity of our proposed screen, we expect to identify
additional mold-active antifungals with novel mechanisms of action for preclinical development.

## Key facts

- **NIH application ID:** 10806511
- **Project number:** 1R21AI176237-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Sarah R. Beattie
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2024-06-12 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806511

## Citation

> US National Institutes of Health, RePORTER application 10806511, HTS with Aspergillus fumigatus for novel, mold-active antifungals (1R21AI176237-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10806511. Licensed CC0.

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