# Mining the Coprophilous Mycobiome for New Cryptococcus Antiinfectives and Antifungal Synergists

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $523,156

## Abstract

Project Summary
This application requests support for studies of coprophilous (dung-colonizing) fungi as sources of
novel natural products (NPs) useful in developing new treatments for Cryptococcus fungal infections--
an area of unmet medical need. The project involves a collaboration between three highly qualified
and productive research groups with a well matched array of complementary experience in discovery
of new bioactive fungal NPs from both academic and industrial perspectives, in evaluation and
development of antifungal agents, and in Cryptococcus pathogenesis. Reasons for targeting
coprophilous fungi as sources of new antifungal NPs include ecological adaptations for microbial
antagonism, genomic evidence for novel pathways, historical under-representation in screening
programs, and positive results from earlier studies conducted independently by two of the Co-PIs. The
approach seeks to avoid inefficiencies inherent in empirical microbial screening paradigms that rely on
testing vast numbers of uncharacterized isolates. A unique, high-quality collection of taxonomically
characterized fungi will be assembled. Strains will be isolated from dung collections from the
Southwestern U.S.—a biodiverse region rich in coprophilous species. Strains will be cultured in arrays
of media using methods selected on the basis of the Co-PI's extensive industrial fermentation
experience. Extracts from the resulting cultures will be multimodally interrogated for anti-Cryptococcus
activity using assays for growth inhibition, differential thermosensitivity, and synergy with existing
antifungal drugs. Selected, NP-rich extracts will be subjected to pre-fractionation. Counterscreens will
be used to de-prioritize extracts and fractions with significant mammalian cytotoxicity. A diverse
subset of the most distinctive and productive species will be genome-sequenced, and gene
inactivation strategies will be employed in efforts to remodel expression of their secondary metabolic
products. Samples showing potent and specific antifungal effects will be subjected to assay-guided
fractionation, and active agents will be identified using spectroscopic methods. Unique information
about coprophilous fungal biology and phylogeny will emerge, and will be combined with assay data
and chemical results to identify fungal lineages likely to afford further new antifungal NPs in ongoing
studies. Active NPs of interest will be produced by scale-up protocols and subjected to in-depth
evaluation, including testing in a validated invertebrate Cryptococcus disease model, and, where
warranted, a mouse model. Mode-of-action studies will be undertaken for the most promising agents.
This project will enable a thorough assessment of hypotheses regarding the promise of these
distinctive fungi as sources of novel antifungal NPs, and offers considerable potential for discovery of
innovative therapeutic agents effective against cryptococcal diseases.

## Key facts

- **NIH application ID:** 9824555
- **Project number:** 5R01GM121458-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** ANDREW ALSPAUGH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $523,156
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9824555

## Citation

> US National Institutes of Health, RePORTER application 9824555, Mining the Coprophilous Mycobiome for New Cryptococcus Antiinfectives and Antifungal Synergists (5R01GM121458-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9824555. Licensed CC0.

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