Fungal infections are a significant public health problem and one difficulty in treatment of these infections is the small number of available antifungal drugs. Moreover, existing treatments suffer both from significant side effects and the frequent appearance of resistant strains. The cell wall is an essential organelle of the fungal cell. Because the cell wall is essential for viability, drugs that inhibit fungal cell wall assembly are potential antifungal agents. Indeed, one major class of current antifungals targets ?-glucan synthase, a key enzyme in cell wall synthesis. In budding yeast, the haploid genomes produced by meiosis are encapsulated by a multi-layered spore wall, which allows spores to resist a variety of environmental stresses. The inner layers of the spore wall are composed of mannan and ?-glucan, similar to the vegetative cell wall. The outer layers of the spore wall are comprised of the polysaccharide chitosan, the polyphenol dityrosine and a third, poorly characterized component termed Chi. These outer spore wall components are absent from vegetative cell walls and primarily responsible for the stress resistance of spores. Importantly, although chitosan and dityrosine are absent from vegetative cell walls in budding yeast, they are present in the walls of pathogenic fungi. The budding yeast spore wall therefore provides an excellent model system to study fungal wall morphogenesis. This grant is focused on understanding the activity and regulation of conserved enzymes involved in synthesis and assembly of different spore wall components with the long-term goal of identifying new targets for antifungal drug development

Public Health Relevance

The fungal cell wall is the interface between the cell and its environment. In pathogenic fungi, proper function of the cell wall is important for survival in the host, and drugs targeting cell wall assembly are effective antifungal agents. The spores of baker's yeast Saccharomyces cerevisiae are not pathogenic but are surrounded by a complex coat, the spore wall, which includes many of the same components found in the walls of pathogenic fungi. We are using spore wall formation as a model system to unravel the biochemistry and genetics of fungal wall assembly. This application focuses on understanding the activity and regulation of enzymes involved in synthesis of different components of the spore wall. The enzymes under study are conserved in pathogenic fungi and, therefore, potential targets for the development of new antifungal drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072540-14
Application #
9768478
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Xu, Jianhua
Project Start
2005-09-12
Project End
2022-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
14
Fiscal Year
2019
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Biochemistry
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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