# Screening Repurposing Libraries for the Identification of Drugs with Novel anti-Coccidioidal Activity

> **NIH NIH U19** · UNIVERSITY OF TEXAS SAN ANTONIO · 2022 · $334,196

## Abstract

Summary (Project 1)
Coccidioidomycosis is a fungal infection caused by Coccidioides posadasii and Coccidioides immitis. It is
estimated that 150,000 new infections occur in the United States each year. The incidence of this infection
continues to rise in endemic regions. There is an urgent need for the development of better therapeutic drugs
against coccidioidomycosis. Currently, the management of coccidioidomycosis includes antifungal agents such
as amphotericin B, fluconazole and itraconazole. However, their toxicity and side effects, and concerns over
the rise of azole-resistant clinical isolates point to an urgent need to develop new agents to combat this
disease. In this project, we propose to screen repurposing libraries in search for drugs with novel activity
against parasitic spherules of C. posadasii, and to apply our newly developed fungal cytological profiling (FCP)
methodology for the identification of potential anti-CM drug candidates. Coccidioides spp. have a unique
dimorphic life cycle characterized by the conversion of arthroconidia to spherules to enter parasitic phase.
Using spherules to screen drug library is more medically relevant compare to saprobic spores/hyphae.
Alteration of critical factor and phenotype (e.g. isotropic growth, cell wall integrity, cell wall remodeling, multi-
nuclear formation) associated with coccidioidal parasitic cycle development can be assessed by FCP for initial
drug library screening and later for drug cellular action discovery. Lead compounds from the drug library
screening will be characterized in vitro for their antifungal activity against relevant clinical Coccidioides isolates
of both C. posadasii and C. immitis, including azole-resistant strains. Subsequent in vivo antifungal efficacy will
be conducted using our newly developed Galleria mellonella model of coccidioidomycosis, which provides a
robust and cost-effective pre-screening system before testing in a more laborious, time-consuming and
expensive rodent models. The leading compounds will be further characterized to gain insights into their
molecular mechanisms of action. Global transcriptomic analyses will identify putative drug-targeted
genes/pathways, which will be further assessed by gene-specific deletion and complementation. This
molecular assessment will be complemented by fungal phenotypic analyses including microscopy (confocal,
TEM) and FCP to gain further insights into the mode of action of each drug candidate. The goal is to identify at
least 4 leading repositionable compounds at the completion of this project for advancing to preclinical
development for chemotherapy against coccidioidomycosis.

## Key facts

- **NIH application ID:** 10363480
- **Project number:** 1U19AI166761-01
- **Recipient organization:** UNIVERSITY OF TEXAS SAN ANTONIO
- **Principal Investigator:** Jieh-Juen Yu
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $334,196
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363480

## Citation

> US National Institutes of Health, RePORTER application 10363480, Screening Repurposing Libraries for the Identification of Drugs with Novel anti-Coccidioidal Activity (1U19AI166761-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10363480. Licensed CC0.

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