Fungal Cell Wall Biosynthesis and Mode of action of Antifungals
Structurally distinct classes of antifungal natural products target enzymes responsible for the formation of the fungal cell wall. The fungal cell wall is composed of two major polysaccharides, chitin and (1,3)-β-D-glucan. These polysaccharides are produced by two distinct polysaccharide syntheses, chitin synthase and (1,3)-β-D-Glucan synthase (GS). We are interested in how these enzymes work to produce the essential polysaccharides, and how these enzymes are inhibited by antifungals.
In this area, our current focus is the mechanism of catalysis and inhibition of (1,3)-β-D-Glucan synthase (GS). GS is a proven target of FDA-approved antifungal drugs (e.g., in micafungin). Due to an emergence of drug resistance and the limited pharmacological behavior of the existing GS inhibitors, there is a persistent interest in developing novel GS inhibitors. However, such development has been hampered by the lack of understanding in the mechanism of GS catalysis and the modes of action of GS inhibitors. We are currently developing chemical probes and novel assay methods to provide mechanistic insights into the GS catalysis and GS-targeting anti fungal mode of action (see Biochemistry 2020).