Revitalising the Antifungal Pipeline with Transition Metals

Fuelled by climate change, antifungal overuse, and a limited pipeline of novel drugs, antifungal resistance is a growing worldwide healthcare concern. To address this crisis, innovative approaches are urgently needed. Transition metal complexes have proven to be a promising yet underexplored compound class. It has been shown that they possess significantly higher hit-rates against fungi compared to purely organic molecules without increased risk of toxicity. In other areas of medicine, metal compounds have already proven key and safe for human use with several being used in the clinics and dozens more in clinical development. However, antifungal applications of metal compounds are still in their infancy. The RAFT project will pursue a systematic exploration, development, and understanding of metalloantifungals. Starting from 3 previously identified metal compound classes we will apply combinatorial synthesis, automation, and machine learning to prepare ~4000 novel metal complexes and study their biological properties. The RAFT team brings together expertise in inorganic chemistry, machine learning, antifungal screening, toxicity assessment, fungal mode of action elucidation, and in vivo evaluation. With these key areas covered, RAFT aims to rapidly identify novel metalloantifungal lead compounds, explore their in vivo properties, and elucidate their mechanisms of action. RAFT will constitute the first systematic, medicinal chemistry-focused exploration of metalloantifungals with the potential to identify new classes of antifungals ready to advance to preclinical studies.