Stress-Activated Protein Kinase Pathways as Potential Targets for the Development of New Antifungals

The World Health Organization WHO considers fungal infections as a significant global risk that necessitates the development of new therapies. The arsenal of antifungals is limited, and the eukaryotic organization of fungi makes it difficult to find selective antifungal targets. In the search for potential targets for the design of new antifungals, the Stress-Activated Protein Kinase (SAPKs) pathways, and specifically, the two-component system, could be a plausible option since this upstream signaling system is absent in metazoans. SAPK pathways are involved in the response and adaptation to different environmental conditions. In pathogenic fungi, these signaling pathways are crucial for virulence, and some of them become activated in response to certain antifungals. Although further experimental evidence is required on the role of SAPKs in antifungal signaling and resistance, the possibility of impairing SAPK signaling by tagging the two-component system can be considered a useful strategy for implementing future antifungal therapies. In particular, the beneficial value of SAPK modulators combined with antifungal drugs should be a preferred line of research. In this review, we focused on the connection between the SAPK pathways and antifungal signaling in the four fungal priority pathogens, Cryptococcus neoformans, Candidozyma (formerly Candida) auris, Aspergillus fumigatus, and Candida albicans, defined by the WHO.