Discovery and functional characterisation of novel combination therapies to combat drug-resistant Candida auris and Aspergillus fumigatus infections

Invasive fungal infections are fatal if not treated, but our ability to treat such diseases is threatened by the emergence of drug-resistant fungi. It is critical to act quickly to combat this threat, and yet very few antifungal drugs are available for clinical use, and the discovery and validation of novel drugs takes many years to accomplish. Conventional approaches to antifungal therapy generally focus on using single antifungal drugs in isolation. However, our team has recently optimized combinations of drugs that demonstrably improve patient survival and prevent the development of resistance in cryptococcal meningitis. Therefore, the aim of this research is to identify combinations of antifungal agents that show great therapeutic promise against two other critically important drug-resistant fungi: Aspergillus fumigatus and Candida auris. The underlying mechanisms that promote the antifungal potency of these combinatorial therapies will be characterised, the frequency of breakthrough drug resistance assessed and the spectrum of activity against other disease-causing fungi will be tested. Central components of our research plan include the validation of promising combinatorial therapies in experimental models of infection, and the analysis of antifungal drugs already in clinical use, with a view to accelerating the translation of promising therapies into the clinic.