PhD position – Developing a novel class of antifungal drugs against a multidrug-resistant fungal pathogen

Invasive fungal infections cause over 2.5 million deaths per year and represent an escalating global health threat, creating an urgent need for new antifungal drugs. The recent emergence of Candida auris, a multidrug-resistant fungal "superbug" responsible for severe hospital outbreaks and high mortality worldwide, is particularly alarming. BET bromodomains are chromatin-binding epigenetic readers that recognize acetylated histones and are essential for fungal viability and virulence. This PhD project aims to establish a novel antifungal strategy by developing small-molecule inhibitors that target BET bromodomains, with a particular focus on Candida auris.

Building on our previous proof-of-concept studies that identified BET bromodomains as promising antifungal targets, we have established molecular and cellular tools to accelerate the discovery of antifungal BET inhibitors [refs.1,2]. These include FRET-based assays for compound screening, humanized Candida strains for on-target validation, and NanoBiT assays to monitor BET bromodomain inhibition directly in fungal cells. This project represents the translational next phase of our research program. It will exploit an AI-guided drug discovery approach called V-SYNTHES (Virtual Synthesis Screening), a structure-based method that enables rapid exploration of ultra-large chemical spaces [ref.3], to develop potent BET inhibitors targeting Candida auris. Inhibitors will be profiled using biophysical, biochemical and cellular assays and structurally characterized in complex with their bromodomain targets. Their activity will then be evaluated for on-target engagement, antifungal efficacy in animal infection models, and resistance development.

The PhD student will play a central role in this research and will be responsible for protein production, biophysical characterization, structure determination of protein-ligand complexes by X-ray crystallography, cellular assays in Candida species, and the assessment of antifungal activity and resistance. This project will be carried out at the Institute of Structural Biology (IBS) in Grenoble, France, in collaboration with experts in medicinal chemistry, medical mycology and fungal epigenetics at the University of Southern California, Grenoble University Hospital and the Institute of Advanced Biosciences (IAB, Grenoble). The project offers an ideal framework for developing expertise in translational research at the interface of structural biology, drug discovery, fungal epigenetics and infectious disease in a highly collaborative environment.

References:
1. Mietton et al., 2017. Nature Communications 8:15482.  https://doi.org/10.1038/ncomms15482
2. Wei et al., 2025. Advanced Science 16:e2404260. https://doi.org/10.1002/advs.202404260
3. Sadybekov et al., 2022 Nature 601:452. https://doi.org/10.1038/s41586-021-04220-9

More information:

https://www.ibs.fr/en/research/assembly-dynamics-and-reactivity/epigenetics-and-molecular-pathways-group-c-petosa/petosa-team/epigenetic-targets-in-pathogenic-fungi/

Research at the Institute of Structural Biology (IBS) aims to understand the molecular mechanisms underlying cellular processes and human disease. Its 300 researchers and staff (including 70 PhD students) are organized into 20 groups that perform interdisciplinary research at the interface of biology, physics and chemistry.

Located on the European Photon and Neutron (EPN) Campus in Grenoble, France (http://www.epn-campus.eu), the IBS is a member of the Partnership for Structural Biology (http://www.psb-grenoble.eu), which provides cutting edge facilities for innovative research in the biomolecular sciences, including on-site access to synchrotron and cryo-EM facilities. 

The IBS is affiliated with the Doctoral School of Chemistry and Life Sciences at the University of Grenoble Alpes (https://edcsv.univ-grenoble-alpes.fr/edcsv), which ranks among the top 6-8 universities in France and the top 150-200 in the world, according to the Shanghai academic ranking of world universities. 

Host lab home page:
https://www.ibs.fr/en/research/assembly-dynamics-and-reactivity/epigenetics-and-molecular-pathways-group-c-petosa/

Living in Grenoble:
http://www.ibs.fr/jobs/about-grenoble/

Highly motivated candidates with a background in chemistry, biochemistry, biology or life sciences and a strong interest in structural biology and drug discovery are invited to apply. Candidates should have a Master’s Degree (or equivalent) or should expect to receive it in the near future. Previous laboratory experience in protein expression and purification, biochemical or biophysical assays, or structural biology approaches is an advantage. Basic programming or data analysis skills are also an asset.