Genetic and chemical validation of sugar nucleotide biosynthesis as a target against Candida albicans (360G-Wellcome-200208_A_15_Z)

The fungal pathogen Candida albicans is one of the leading causes of invasive fungal disease. The incidence of invasive Candidiasis has remained high due to a combination of a rising population of immunocompromised patients and the emerge of resistance against a small arsenal of only partially effective antifungal drugs. There is thus an urgent need for novel, properly genetically and chemically validated, drug targets. The Candida cell wall consists of chitin, glucan and mannan. Despite an emerging understanding of the complex membrane proteins involved in synthesis of these polymers, targeting them has proven difficult. Instead, in this proposal we aim to target the "Achilles heel" of cell wall synthesis – the production of the sugar nucleotides UDP-Glc, UDP-GlcNAc and GDP-Man that will cut deep into the essential wall biosynthetic machinery. Using state-of-the-art techniques we will genetically, structurally and chemically validate C. albicans enzymes from these sugar nucleotide biosynthetic pathways as antifungal targets. The output will be: 1) A significant increase in our molecular understanding of these enzymes, 2) A collection of novel chemical tools for use by the fungal scientific community, and 3) A portfolio of targets (and associated tools) that serve as a springboard for novel antifungal drug discovery.