Since fungi are eukaryotic and evolved in close association with their mammalian hosts, most essential fungal molecular targets for drug development bear a considerable risk of cross-target host toxicity. The current arsenal of antifungal drugs and therapies are limited in number and diversity, and their efficacy is severely hampered by host toxicity, fungistatic rather than fungicidal activity and drug resistance. our overarching goal is to identify novel fungal-specific targets for the development of fungal-selective, pan-antifungal drugs. To reduce our reliance on pathogen-targeted agents, we propose an integrated approach that will combine therapeutic interventions to boost hosts’ anti-fungal immune response and selective targeting of fungal essential pathways.
Targeting regulated cell death pathways in fungal pathogenesis
A promising and yet unexploited strategy to combat fungal infections is pharmacologic targeting of fungal cell death pathways.
We discovered that mammalian immune surveillance against inhaled fungal conidia involves targeting of an apoptosis-like regulated cell death (RCD) pathway in fungal cells. In response, the fungal anti-RCD machinery, mediated by a protein termed Bir1, counteracts host defenses and protects the fungus from host-induced RCD by facilitating phagosomal escape and invasive aspergillosis (IA).