Antifungal discovery: Unlocking the hidden potential of fungal genomes

Abstract

Fungal infections are becoming more common around the world and can vary in severity from inconvenient to lethal. Effective antifungal agents exist, but resistant fungal strains are becoming more prevalent, highlighting the need for novel antifungal agents. Microorganisms in the wild compete with each other for resources and territory. To fight off other organisms they produce molecules called secondary metabolites that can have antimicrobial properties. This makes secondary metabolites an interesting source of novel compounds in drug discovery. This review aims to describe the way we can discover these novel antifungal drugs. Fungi produce a lot of secondary metabolites. They are produced by enzymes that are expressed by different genes that are often found together in a cluster. These clusters are called biosynthetic gene clusters. It is possible to scan genomes of fungi for the presence of these biosynthetic gene clusters, based on the presence of certain genes that are known to code for biosynthetic enzymes. Gene clusters that encode for secondary metabolites with antimicrobial activity share certain characteristics like the presence of resistance genes or duplications of essential genes. These characteristics allow for identification of gene clusters that are potentially antifungal. Gene clusters of interest can be expressed in the host or in another organism in order to investigate the secondary metabolite that is produces. To possibly improve the qualities of the new compound as an antifungal agent, there are ways to modify the secondary metabolite by changing the composition of the biosynthetic gene cluster. Altogether these methods form a pipeline for discovering novel antifungal agents by analysing fungal genomes.