Regulation of the biosynthesis of the cell wall skeleton of Candida albicans. (360G-Wellcome-086827_Z_08_Z)

Chitin is an essential molecule in the cell walls of all fungi and invertebrates that challenge human health. In fungi, chitin and a second polysaccharide, beta(1,3)-glucan, form the core of the wall skeleton, and since neither molecule is found in humans they represent specific targets for chemotherapy. However cell wall synthesis is carefully regulated by fungi and they have elaborate salvage mechanisms to protect the integrity of their cell walls. This project investigates the regulation of c hitin synthesis in the fungal pathogen Candida albicans in terms of newly identified mechanisms that (a) regulate the normal localisation of chitin synthase enzymes and (b) modify wall synthesis to rescue the cell under conditions of stress. The specific goals are therefore: (i) to exploit and test the hypothesis stemming from our observation that spatial control of chitin synthesis is regulated by phosphorylation of chitin synthases; (ii) to investigate the spatial regulation of chitin synthesi s and septum formation under conditions that rescue cells from cell wall damaging agents; (iii) to test whether combinations of chitin synthase and cell wall beta(1,3)-glucan synthase inhibitors can overcome the rescue mechanisms in vivo leading to antifungal chemotherapies of enhanced efficacy.