V-SYNTHES-guided discovery of BET bromodomain inhibitors : a novel antifungal strategy against Candida auris

New antifungal strategies are urgently needed to combat Candida auris, an emerging multidrug-resistant fungal "superbug" responsible for severe hospital outbreaks and high-mortality infections. Our previous proof-of-concept studies in Candida albicans and Candida glabrata established that fungal BET bromodomains – chromatin-binding modules that recognize acetylated histones – represent promising new antifungal targets. We have developed an advanced set of molecular and cellular tools to accelerate antifungal BET inhibitor discovery, including 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 PhD project represents the translational next phase of our research program. It will exploit the AI-guided V-SYNTHES drug discovery approach – a cutting-edge virtual screening and design framework – to develop highly potent BET inhibitors targeting C. auris. Inhibitors will be profiled in biophysical, biochemical and cellular assays, structurally characterized in complex with their bromodomain targets, and validated for on-target activity in C. auris and antifungal efficacy in animal infection models. They will also be used to explore the emergence of resistance to BET inhibition. This project combines an original antifungal strategy with an innovative methodological approach, offering a unique framework for training in interdisciplinary and translational research.

Magneto-mechanical stimulation for the selective destruction of pancreatic cancer cells while sparing healthy cells

A novel approach for selectively destroying cancer cells is being developed through a collaboration between the BIOMICS biology laboratory and the SPINTEC magnetism laboratory, both part of the IRIG Institute. This method employs magnetic particles dispersed among cancer cells, which are set into low-frequency vibration (1–20 Hz) by an applied rotating magnetic field. The resulting mechanical stress induces controlled cell death (apoptosis) in the targeted cells.
The effect has been demonstrated in vitro across various cancer cell types—including glioma, pancreatic, and renal cells—in 2D cultures, as well as in 3D pancreatic cancer spheroids (tumoroids) and healthy pancreatic organoids. These 3D models, which more closely mimic the structure and organization of real biological tissues, facilitate the transition to in vivo studies and reduce reliance on animal models. Preliminary findings indicate that pancreatic cancer cells exhibit a higher affinity for magnetic particles and are more sensitive to mechanical stress than healthy cells, enabling selective destruction of cancer cells while sparing healthy tissue.
The next phase will involve confirming this specificity in mixed spheroids (containing both cancerous and healthy cells), statistically quantifying the results, and elucidating the mechanobiological mechanisms underlying cell death. These promising findings pave the way for an innovative biomedical approach to cancer treatment.