Aspergillus fumigatus is the most prevalent airborne fungal pathogen causing invasive fungal infections in immunosuppressed individuals. Limitations in antifungal therapy arise from nonspecific symptoms of infection, poor diagnostics and comparatively few options for treatment. The aim of this study is to explore the metabolism of A. fumigatus on a comprehensive scale as essential virulence determinant to generate a collection of A. fumigatus strains with a focus on primary metabolism to target fungal pathways that are absent in mammals.
One example of such a pathway, which we currently investigate, is the biosynthesis of histidine. Histidine is an essential amino acid for all living organisms. Bacteria, plants und fungi are able to produce histidine while animals and humans are not and satisfy their demand via nutritional uptake. Remarkably our data show that the loss of histidine biosynthesis leads to virulence attenuation of A. fumigatus in animal models including Galleria mellonella and mouse.
The projects idea is to generate a collection of A. fumigatus strains covering its biosynthetic landscape, with a focus on primary metabolism to target fungal-specific activities. The mutant strains will be subjected to extensive phenotypic characterization, comprising virulence studies to analyze infectivity in established animal models of aspergillosis. This systematically applied metabolic network approach will yield novel antifungal drug targets based on the metabolism of A. fumigatus that will serve as promising candidates for therapeutic intervention to fight fungal infections.
