Small Molecule-Based Structure-Function Analysis of Fungal Chitin Synthase
Chitin is an essential fungal cell wall polysaccharide produced by synthases of the GT2 family. Chitin synthase activity is required for cell wall integrity and filamentous development, with the latter being a virulence determinant in the pathogenic fungus Candida albicans. Chitin synthase is inhibited by the drug nikkomycin Z and further represents a promising target for the identification of new antifungal small molecules. Towards this goal, we are reconstituting chitin synthase activity in proteoliposeomes for structure-function analysis. Incorporating computational models of liganded enzyme, we will identify and screen a candidate small molecule library for inhibition of chitin synthase. Identified small molecules will be assessed for antifungal activity through assays for filamentous growth and biofilm formation in C. albicans. In sum, this work holds the potential to reveal new antifungal agents critical for the care of immunocompromised patients and pre-term infants.
Presented at the Yeast Genetics and Molecular Biology Meeting / Stanford University.
Published article in PLoS Genetics.