Inhibition by proxy: targeting fungal chitin synthesis through sugar nucleotide biosynthesis. (360G-Wellcome-105772_Z_14_Z)

A limited therapeutic arsenal against increasing clinical disease due to opportunistic pathogenic fungi necessitates urgent characterisation of novel antifungal targets. The fungal cell wall of Aspergillus fumigatus represents a drug target: this dynamic and multi-layered structure is almost entirely built of polysaccharides such as chitin and glucan that are absent from the host. Chitin synthases convert the sugar nucleotide precursor UDP-N-acetyl-D-glucosamine (UDP-GlcNAc) to a linear core of chitin that is fundamental for survival. A proxy target for chitin synthesis, glucosamine-6-phosphate N-acetyltransferase (Gna1), plays a key role in de novo UDP-GlcNAc biosynthesis. Two equally important hurdles any potential drug target must overcome during initial assessment relate to (1) phenotype and (2) ligandabiilty i.e. are chemical-protein interactions possible? Fragment screening assesses the latter and together with x-ray crystallography I have have discovered a fungal specific bindi ng pocket on the target protein Gna1 next to the active site. In vitro growth of my gna1 knockout is only possible with exogenous GlcNAc. Building on this exciting body of preliminary data with the support of the Wellcome Trust I will investigate: 1. Contribution of GNA1 to pathogenicity using invertebrate and murine infection models. 2. Elaboration of promising hits into inhibitors with in vitro fungicidal activity.