# ROLE OF CELL WALL INTEGRITY IN ECHINOCANDIN RESISTANCE IN C. NEOFORMANS

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $363,050

## Abstract

Cryptococcus neoformans is a pathogenic fungus that is found world-wide and causes
meningioencephalitis, particularly in immunocompromised individuals. It is invariably fatal unless
treated, and the current antifungals are inadequate to effectively cure this disease, due to
inherent toxicities, the inability to kill the fungus and prevent relapse, or innate resistance to the
class of antifungals. Recent studies have indicated that there are over 1,000,000 new cases of
cryptococcosis in the world each year, which results in over 600,000 deaths. New agents to
treat Cryptococcus are needed, and the fungal cell wall is an attractive target, since it is unique
to fungi and absent in humans. Echinocandins are a class of antifungals that target glucan
synthesis in the cell wall. Cryptococcus is naturally resistant to the echinocandins. We have
shown that disruption of the cell wall integrity (CWI) signaling pathway causes Cryptococcus to
become highly sensitive to echinocandins, and identified candidate transcription factors that
may play a role in echinocandin resistance. This pathway is the major pathway that impacts cell
wall and is dependent on protein kinase C (Pkc1). The CWI/PKC1 pathway plays a key role in
response to heat shock, oxidative and nitrosative stress, and cell wall inhibitors. Our preliminary
data suggests that this pathway is part of a highly connected network that controls cell wall
biosynthesis, repair and remodeling. The major goal of this project is to define the
mechanism(s) by which cell wall integrity is maintained in response to specific cell wall
inhibitors, including echinocandins and to identify potential gene targets for antifungals with
synergy to echinocandins. There are three specific aims: In the first aim, we will define the role
of the cell wall integrity pathway in echinocandin resistance using genomic and network analysis
approaches. In the second aim, we will identify the genes essential to cell wall integrity and that
contribute to echinocandin resistance by screening large deletion sets for specific phenotypes.
In the third aim, we will assess the functional interactions of the cell wall integrity components.
In this highly collaborative project, we propose to use our complementary expertise to integrate
genetic, phenotypic and biochemical data to identify and characterize the network of interactions
governing cell wall homeostasis in C. neoformans. This will significantly advance our
understanding of cell wall maintenance and remodeling in a human pathogen and will provide
multiple targets for designing specific antifungal drugs that are less likely to be toxic in
mammals.

## Key facts

- **NIH application ID:** 10626232
- **Project number:** 7R01AI123407-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Maureen J Donlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $363,050
- **Award type:** 7
- **Project period:** 2017-06-26 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10626232

## Citation

> US National Institutes of Health, RePORTER application 10626232, ROLE OF CELL WALL INTEGRITY IN ECHINOCANDIN RESISTANCE IN C. NEOFORMANS (7R01AI123407-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10626232. Licensed CC0.

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