EvoTolRes · Divergent evolution of drug resistance and tolerance in a fungal pathogen

Invasive fungal infections remain a major global health threat, with mortality rates approaching 50% despite existing treatments. However, treatment failure in fungal infection is frequently not due to classical drug resistance which is often caused by genetic mutations that block drug action. Instead, recurrent fungal infections are typically driven by antifungal tolerance: a poorly understood phenomenon where a subpopulation of cells survives and grows slowly under drug exposure. The evolutionary drivers and molecular mechanisms of antifungal tolerance, and how it relates to resistance, remain largely unknown. This project will dissect the tolerance-resistance evolutionary pathways in Candida albicans, a WHO-listed fungal priority pathogen. I will leverage a unique resource of 1,800 clinical strains from my host and collaborator labs, alongside cutting-edge approaches, including large-scale experimental evolution, high-throughput multi-omics (genomics, proteomics, metabolomics), and CRISPR-Cas9 gene editing. My key objectives are to: (1) identify the molecular signatures that distinguish between the development of tolerance and resistance, (2) determine whether stress responses, metabolic reprogramming, or proteome shifts, establish permissive conditions for subsequent genetic adjustments during evolution, and (3) develop novel strategies to disrupt tolerance evolution, such as adjuvant therapies and collateral sensitivity approaches. Hosted in the world-renowned Ralser lab at Charité, I will gain advanced training in systems biology and high-throughput analysis, while contributing my expertise in microbial evolution. Through targeted public engagement and open dissemination of findings, this project will raise awareness of antifungal drug failure and foster scientific collaboration. The fellowship will strengthen my path toward independence as a group leader in microbial evolutionary biology, while addressing one of the most urgent challenges in global health.