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

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $47,706

## Abstract

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:** 10168436
- **Project number:** 5R01AI123407-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Maureen J Donlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $47,706
- **Award type:** 5
- **Project period:** 2017-06-26 → 2022-02-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168436

## Citation

> US National Institutes of Health, RePORTER application 10168436, ROLE OF CELL WALL INTEGRITY IN ECHINOCANDIN RESISTANCE IN C. NEOFORMANS (5R01AI123407-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10168436. Licensed CC0.

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