Essential Genes inAspergillus fumigatus

Abstract

This chapter discusses recent developments in the identification of essential genes and validation of potential antifungal drug targets in Aspergillus fumigatus. Essential genes were identified based on (i) the inability to construct haploid insertional mutants or (ii) identification of temperature-sensitive conditional mutants. The compendium of recently defined conserved essential genes in Saccharomyces cerevisiae, Candida albicans, and other fungi has provided important insights for predicting essential genes in A. fumigatus. Essential genes that are required for fungal survival and growth provide potential antifungal drug targets. A. fumigatus genes which have been experimentally demonstrated to be essential for growth are summarized. This essential gene set includes genes involved in various biological and biochemical functions, such as amino acid, cell wall, ergosterol, heme, and lipid biosynthesis, as well as cell cycle control, cellular metabolism, protein transport, ribosome biogenesis, and RNA splicing. Additional A. fumigatus essential genes involved in ergosterol biosynthesis include ERG10, ERG12, ERG7, ERG8, and ERG20 and as such, provide new targets for therapeutic intervention. Currently, identification of A. fumigatus essential genes largely depends on the following four approaches: conventional gene deletion and disruption, parasexual genetics, RNAi knockdown, and conditional promoter replacement strategies. Completion of the A. fumigatus genome sequence, however, combined with current molecular genetic strategies and their inevitable refinements, has now made large-scale genetic analysis of A. fumigatus possible for the first time, thus expanding our knowledge of its biology, pathogenesis, and potential antifungal targets.