FunHitDisco: A Fungal Hit Discovery Platform
( FunHitDisco )

Therapeutics

Research Project: 2025-04-01 - 2028-03-31
Total sum awarded: €1 329 273

The increasing threat of treatment-resistant fungal disease is of significant societal concern. Furthermore, with only a limited number of drug classes available for treatment, it is imperative to focus drug discovery efforts on both new compound classes and under-explored fungal protein targets. Accordingly, in the current project we will employ two innovative high throughput screening technologies, elicitor screening and mRNA display, to discover antifungal hit compounds for development. Elicitor screening utilises small molecule libraries to unlock suppressed bacterial biosynthetic pathways for producing bioactive molecules. By combining this with a phenotypic fungal growth inhibition assay, we can efficiently explore this natural product “dark matter” for hit compounds. Our second approach, mRNA display, is target-orientated. It uses cell-free transcription and translation systems to generate RNA-tagged, large peptide libraries for screening against protein targets. The peptide chemical space is expanded by including macrocyclization and non-standard building blocks to improve drug-likeness. In subsequent medicinal chemistry, hits will be optimised for antifungal potency, toxicity and favourable drug-like properties. Furthermore, we will perform target identification and explore mode of action with biochemical assays and crystallography. Our goal is to generate validated hits corresponding to novel antifungal classes or those that act against under-explored protein targets, and to push these compounds for further development towards the clinic.

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  • Lindon Moodie, Uppsala University, Sweden (Coordinator)
  • Luke Robertson, Uppsala University, Sweden (Partner)
  • Seino Jongkees, Vrije Universiteit Amsterdam, Netherlands (Partner)
  • Maria Klimecka, University of Warsaw, Poland (Partner)
  • Francesca Bugli, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Italy (Partner)

Treatment resistant fungal infections contribute to millions of deaths on a global scale, and significantly impair the standard of living of many. Despite a century of efforts from modern medicine, clinicians have only a limited array of antifungal drug classes for deployment. To further complicate this, fungal pathogens are developing resistance to these drugs. We need new classes of drugs and those that act against different targets to our current drugs. The alternative, slightly modifying known drugs, will only buy time until resistance mechanisms catch up. To help alleviate this problem we will establish FunHitDisco: A Fungal Hit Discovery Platform. In this, we will use new methods that offer access to chemicals very different from what is currently in use. One of these approaches will use collections of the chemicals produced by bacteria in their fight against fungi, their rivals in the biosphere. Production of these ‘chemical weapons’ will be triggered by adding stimulating signals called elicitors to trick the bacteria into thinking they are in competition. The other approach uses a highly modular class of molecule called peptides, and works by generating extremely large collections of these. These are barcoded with DNA, and this lets us identify which are active. This essentially uses evolution on the molecule level to find new drugs. The molecules identified will then be chemically optimised to improve their potency and drug like properties, and their mode of action will be investigated; beginning their journey towards the clinic.

Call

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