Revitalising the Antifungal Pipeline with Transition Metals
( RAFT )

Interventions

Therapeutics

Research Project: 2025-04-01 - 2028-03-31
Total sum awarded: €1 008 304

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.

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  • Angelo Frei, University of York, United Kingdom (Coordinator)
  • Mike Bromley, University of Manchester, United Kingdom (Partner)
  • Michaela Wenzel, Chalmers University of Technology, Sweden (Partner)
  • Amy K. Cain, Macquarie University, Australia (Partner)

Antibiotic resistance is a well-known problem, but what is less talked about is the rise of drug-resistant fungal infections. These infections, caused by organisms like moulds and yeasts, are becoming harder to treat because we have fewer effective medicines for them. This is because these organisms have developed resistance to our current medicines over time and we have not come up with enough new drugs in recent times. In this work we are proposing to explore a potential solution in an unexpected place: metal compounds. These compounds, which have been used in medicine for a long time, offer a new approach to fighting fungal infections. They work differently from traditional drugs, targeting fungi in unique ways. Recent studies have shown promising results, with some metal compounds successfully killing drug-resistant fungi in lab tests and even in animal models. However, we are only at the beginning, and we do not know yet which metal compounds will be the best antifungals. To explore this further, our team aims do delve deeper into the potential of these metal compounds. Using new techniques and adapting machine learning approaches we will create and test thousands of new metal compounds to see if any are effective against fungal infections. We will then further study these compounds to understand how they are able to kill fungi and the best ones will be tested in animal models. If successful, this work could lead to the development of much-needed new treatments for these stubborn infections.

Call

2024 - Interventions moving forward to promote action to counteract the emergence and spread of bacterial and fungal resistance and to improve treatments