# Elucidating the molecular mechanisms of septin-dependent drug response to the antifungal caspofungin in the human pathogen Aspergillus fumigatus

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $435,577

## Abstract

ABSTRACT
 Aspergillus fumigatus is the main etiological agent of invasive aspergillosis (IA). IA primarily affects
immunocompromised patients and carries a mortality rate as high as 60%. Due to the significant increase in
the immunocompromised patient population and the emergence of azole-resistant A. fumigatus, a critical
understanding of A. fumigatus biology is needed to improve patient outcomes. Caspofungin, which
targets fungal cell wall synthesis, is a second-line therapy for invasive aspergillosis. However, this antifungal is
fungistatic rather than fungicidal. Comprehending how A. fumigatus responds to caspofungin can lead to a
much-needed breakthrough, improving the caspofungin treatment success.
 Septins are a conserved family of GTP-binding proteins. Septins interact with each other to form higher-
order structures and recruit other proteins. Septins play roles in recognizing micron-scale plasma membrane
curvature, cytokinesis, cell cycle progression, and response to cell wall stress. The overall aim of our R01
application is to determine the molecular mechanism that contributes to the septin-dependent fungal response
to caspofungin. We hypothesize that septin AspB mediates Aspergillus fumigatus fungistatic response
to caspofungin. Our hypothesis is supported by 1) an increase in susceptibility to caspofungin after deletion of
core septin genes in various fungal pathogens, 2) the increase in the number of visible septin structures after
exposure to caspofungin, 3) protein pulldowns that show septin complex together with components of the cell
wall integrity pathway, and 4) preliminary proteomics analysis that shows differential septin-protein interactions
after exposure to caspofungin.
 We will test our central hypothesis in three aims: Aim 1. Determine the role of the septin cytoskeleton in
response to caspofungin, Aim 2. Define septin-protein interactions after caspofungin exposure and Aim
3. Elucidate the role of the septin cytoskeleton in the cell wall integrity pathway.
 Completing this grant will close a critical gap in understanding how fungal pathogens respond to
caspofungin and how septins facilitate this. With this knowledge, novel therapeutic approaches can be
designed to ultimately improve the outcome of caspofungin treatment.

## Key facts

- **NIH application ID:** 10879480
- **Project number:** 1R01AI165656-01A1
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Jose Vargas-Muniz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $435,577
- **Award type:** 1
- **Project period:** 2024-07-17 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879480

## Citation

> US National Institutes of Health, RePORTER application 10879480, Elucidating the molecular mechanisms of septin-dependent drug response to the antifungal caspofungin in the human pathogen Aspergillus fumigatus (1R01AI165656-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879480. Licensed CC0.

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