Antifungal Agents: chitin synthase inhibitors

Chitin is the second most abundant polysaccharide in nature, nascent linear chains of beta(1,4) linked N-acetyl glucosamine, synthesised by chitin synthase enzymes, become hydrogen bonded together to form strong chitin fibrils. Chitin is found in insect exoskeletons, shells of crustaceans as well as the fungal cell wall. Therefore, the development of chitin synthase inhibitors has a wide range of commercial applications. This project will initially focus on developing chitin synthase inhibitors as a therapeutic treatment for patients with life-threatening invasive fungal infections. Chitin (or its deacetylated form chitosan) is ubiquitous in the walls of fungi, is required for fungal viability, yet is absent from host mammalian cells making it an ideal target for drug development. The most recent class of antifungal drug introduced into the clinic is the echinocandins that target synthesis of another cell wall polysaccharide beta(1,3) glucan. Recently we have shown that fungal cells which have elevated chitin levels are more tolerant to echinocandin drugs suggesting that activation of chitin synthesis allows fungi to survive when glucan synthesis is inhibited. However, genetic blockade of chitin biosynthesis prevented echinocandin tolerance. Therefore, combinations of chitin and glucan synthase inhibitors would be potent therapies for a wide range of fungal infections.

In fungi, chitin is synthesised by a multi-gene family of transmembrane chitin synthase (Chs) isoenzymes that share a common catalytic domain. This project will use a high throughput assay, developed at the University of Dundee, to screen for novel inhibitors of chitin synthase.

Project Team:

Dr Carol Munro, Prof Daan van Aalten and Dr Helge Dorfmueller (University of Dundee)