The goal of the proposed research is to identify the structural characteristics of fungal cell walls involved in virulence and drug response. Invasive fungal infection results in fatal diseases in individuals with immunodeficiency. Existing antifungal drugs have been mainly designed to target fungal cell membranes, but they also bind to human cell membranes, thus causing severe side effects. Recent efforts have been devoted to developing agents that bind fungal cell walls because they contain carbohydrates, for example, chitins and ?- glucans, that are absent in human. Such biomolecules, however, evade high-resolution structural characterization as they are typically insoluble and polymorphic in structure. Recently, we initiated a project to investigate the native cell wall structure of Aspergillus fumigatus, a major pathogenic fungus causing invasive aspergillosis, using solid-state NMR spectroscopy. This method provides atomic-level insight into the supramolecular assembly of carbohydrates and proteins in native fungal cell walls with minimal perturbation. The central hypothesis is that the large-scale spatial rearrangement of biomolecules directly regulates fungal virulence and drug resistance. This hypothesis will be tested by pursuing two specific aims: 1) identify the structural variation of cell walls from pathogenic and non-pathogenic fungi, and between the young and aged fungi; 2) elucidate the molecular effects of antifungal drugs on the cell wall structure of wildtype and drug-resistant strains. The expected outcomes include the first set of comparative models of Aspergillus cell wall structure with dependence on four variables: fungal type and pathogenicity, age, drug concentration, and genetic mutants. The approaches established in this project will be widely applicable to investigations of many other fungal pathogens. This combined effort of biophysical methods, carbohydrate chemistry, and medical mycology presents a unique and novel contribution as it bridges the gap between molecular structures with phenotype and drug effects. The dynamic and comprehensive view of the functional structure of fungal cell wall obtained here, in the long term, will facilitate the discovery and evaluation of novel therapies that can effectively inhibit a broad spectrum of pathogenic fungi by targeting their cell wall structure or biosynthesis.

Public Health Relevance

The high mortality of invasive fungal infections and the limited number and inefficacy of existing antifungals necessitate the development of better drugs. The fungal cell wall is an attractive drug target as it contains polysaccharides absent in humans, however, its complex structure is difficult to characterize with high-resolution. This proposal seeks to identify the structural determinants of fungal virulence and elucidate the molecular effect of antifungal drugs on the cell wall structure of a pathogenic fungus Aspergillus fumigatus, which will fundamentally advance the field of medical mycology and provide the structural foundation for designing antifungal drugs targeting fungal cell walls.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI149289-02
Application #
10098297
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Love, Dona
Project Start
2020-02-05
Project End
2022-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Louisiana State University A&M Col Baton Rouge
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
075050765
City
Baton Rouge
State
LA
Country
United States
Zip Code
70803