# Revealing the Cell Wall Organization of Fungal Pathogens and Structural Responses to Antifungal Drugs Using Cellular Solid-State NMR

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2024 · $376,740

## Abstract

Project Summary
Invasive fungal infection has high occurrence and mortality among immunocompromised patients. Most of
the currently available antifungal agents targeting the cell membrane have limited efficacy, relatively high
toxicity, and an observed increase in drug resistance. The cell wall of fungal pathogens is a promising target
for antifungal drugs due to its absence in humans. Still, such efforts have been hindered by our inadequate
knowledge of the cell wall organization. The long-term goal of our research is to understand the structures
of cell walls of prevalent fungal pathogens at the molecular level to promote the development of wall-
targeting therapeutics against infections. This project aims to develop solid-state nuclear magnetic
resonance (ssNMR) technology that allows understanding the nanoscale remodeling of fungal cell wall
structures involved in fungal virulence and drug resistance. The central hypothesis is that the fungal cell
walls’ structural dynamics and mechanical properties are major factors contributing to virulence and drug
resistance. This central hypothesis will be tested by three specific aims. We will interrogate the polymorphic
structure of major structural polysaccharides and their supramolecular packing in the cell walls of three major
fungal pathogens, including Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans.
Second, we will determine the structural dynamics of the cell wall and the remodeling process of the
biopolymer composite induced by antifungal echinocandins and nikkomycin that target, respectively, β-
glucan and chitin, two of the major cell wall components. Third, we will examine cell wall structures of
naturally occurring mutant strains of A. fumigatus and C. albicans showing modulated susceptibility to
antifungal agents and the superbug Candida auris to identify the structural mechanisms underlying altered
drug responses. We will pursue these aims by establishing an innovative approach that combines ssNMR
and dynamic nuclear polarization (DNP) techniques to enable high-resolution and non-destructive
characterization of intact and living fungal cells. The project is significant because it will identify the essential
carbohydrate components and their structures or packing interfaces that serve as the potential targets for
discovering novel antifungal compounds with broad spectrums and improved efficacy. Our efforts will yield
a collection of structural diagrams of cell walls across three major fungal pathogens and their responses to
antifungal agents and mutations. The research will define a new biophysical direction bridging the long-
standing gap between biomedical observations of fungal phenotypes and the fundamental understanding of
structures and interactions of biomolecules at atomic levels. The methodology established here will also
permit the high-resolution assessment of structural effects of antifungal agents that are available or being
developed, which will revolutio...

## Key facts

- **NIH application ID:** 10762985
- **Project number:** 5R01AI173270-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Tuo Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $376,740
- **Award type:** 5
- **Project period:** 2023-01-10 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762985

## Citation

> US National Institutes of Health, RePORTER application 10762985, Revealing the Cell Wall Organization of Fungal Pathogens and Structural Responses to Antifungal Drugs Using Cellular Solid-State NMR (5R01AI173270-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10762985. Licensed CC0.

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