Compromising UDP-sugar nucleotide biosynthesis attenuates Candida albicans viability, virulence and drug sensitivity

Candida albicans is an opportunistic fungal pathogen that can cause a variety of superficial and life-threatening systemic infections. Relatively few clinically effective antifungal therapies are available, and the increasing prevalence of antifungal drug resistance poses a serious threat in treating these infections. Target validation of biochemical pathways that are essential for fungal growth offers an approach towards the design of novel antifungal drugs that address the growing requirement for new antifungal therapies. Therefore, we used the GRACE library of conditional mutants of C. albicans to explore enzymes in the sugar nucleotide biosynthesis pathway as potential drug targets. This pathway provides UDP-N-acetylglucosamine (UDP-GlcNAc), UDP-glucose (UDP-Glc) and GDP-mannose (GDP-Man) substrates for the synthesis of the essential cell wall polymers, chitin, β-glucan(s) and mannan(s). We show that the genes encoding GDP-mannose pyrophosphorylase (SRB1/PSA1/VIG9), UTP-glucose-1-phosphaturidyl transferase (UGP1), phosphoglucose isomerase (PGI1) and glucosamine-6-phosphate synthase (GFA1) are critical for growth, biofilm formation and virulence in C. albicans. Genes encoding other enzymes in the sugar nucleotide biosynthetic pathway (namely AGM1, PMM1, PMI1, GNA1 and UAP1) were not essential for growth but were required for biofilm formation, tissue invasion and virulence. Repression of genes that encode these enzymes also resulted in hypersensitivity to a range of antifungal drugs as well as oxidative and cell wall stressors. These data underline the potential for augmenting antifungal drug development by targeting these enzymes in the treatment of C. albicans infections.