Fungal Cell Wall Biosynthesis and Mode of action of Antifungals
Many 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, and how antifungals inhibit these enzymes.
In this area, our current focus is the mechanism of catalysis, regulation, and inhibition of chitin synthase (CHS) and (1,3)-β-D-Glucan synthase (GS). GS is a proven target of FDA-approved antifungal drugs (e.g., micafungin). Due to the 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 our limited understanding of the mechanism of GS catalysis and inhibition. We are currently developing chemical probes and novel assay methods to provide mechanistic insights into the GS catalysis and GS-targeting antifungal mode of action (see Biochemistry 2020).
CHS, on the other hand, has been targeted by peptidylnucleoside (PN) antifungals, represented by nikkomycins and polyoxins. However, the existing CHS inhibitors are specific to certain classes of CHS, which limits the potency and spectra of these compounds. The long-term goal of this project is to discover and develop CHS inhibitors active against multiple classes of CHS with broader spectrum antifungal activities. To this end, we are currently characterizing the structure and function of CHS from pathogenic fungi and developing inhibitors against them (see Nat. Struct. Mol. Biol. 2022).
