Opportunistic invasive fungal infections (IFIs) carry high morbidity and mortality for those with co-morbidities, especially the immunocompromised, such as transplant and AIDS patients. Despite treatment with the best available antifungal drugs, approximately 50% of the patients with IFIs die. The need for new, potent and inexpensive fungicides is urgent due to innate and acquired resistance to antifungal agents. This project will meet this need. We will use high-resolution structures of the antifungal target lanosterol 14α-demethylase (LDM) from a range of fungal species and humans, together with yeast-based assays, clinical isolates of fungal pathogens, and animal trials, to elucidate key features conferring antifungal specificity and that optimize broad-spectrum antifungal candidates in readiness for drug development by the pharmaceutical industry. Drug resistance will be addressed using in-house technology to identify LDM-directed fungicides and mixtures that improve potency and avoid the emergence of drug target- and drug efflux-mediated antifungal resistance.