Infections caused by common human pathogenic fungi result in over 1.5 million deaths worldwide every year. The main source of this problem is the increasing emergence of species resistant to widely used antifungal agents. They emerge due to selection events induced by the over-use of these agents in agriculture and medicine. This issue could be tackled by targeting mechanisms important for fungal pathogenicity and survival. The regulation of carbon metabolic pathways is crucial to adapting cellular processes, like energy production and cellular component synthesis, to changing environmental conditions for fungal cells.

One of the most prevalent human pathogenic fungi is the airborne saprophytic fungus Aspergillus fumigatus. This pathogen can cause infections in the lower respiratory tract, lungs, sinuses and skin. Aspergillus fumigatus uses a complex signalling network system to make changes in carbon metabolic processes when exposed to osmotic or cell wall stress. These pathways are key to infecting the host and surviving in the human organism. Many existing antifungal drugs, like azoles and echinocandins, target biomolecules in these pathways. However, the problem of increasing A. fumigatus resistance to the available drugs is causing a surge of deaths among immunodeficient patients with invasive aspergillosis.

Knowledge about the networks that regulate core cellular processes in A. fumigatus can be used to look for new fungicide targets and help reduce the problem of antifungal drug resistance. Here, we designed two Boolean models that show how carbon metabolism signalling pathways respond to osmotic and cell wall stress in A. fumigatus. Then, we used these models to identify new antifungal drug targets in these networks. Our results suggest that osmotic and cell wall stress both induce the synthesis of carbon-based cell wall components in order to defend against stressors. Moreover, we show how these processes can be disrupted by targeting the RlmA transcription factor under cell wall stress and the SskB kinase under osmotic stress. Our models show that targetting RlmA of the cell wall integrity pathway is a way to inhibit 1,3-beta-D glucan synthase and increase echinocandin drug effectiveness, while targetting SskB of the HOG pathway is a possible way to inhibit fungal cell wall component synthesis.