Invasive fungal infections kill an estimated 1.6 million people each year – as many deaths as are caused by tuberculosis or malaria. Currently, only four drug classes are available to treat these infections (polyenes, azoles, flucytosine and echinocandins). This limited repertoire of antifungal drugs, combined with an alarming rise in drug-resistant fungal strains, has created an urgent need for novel therapeutic agents. In the developed world, the most common fungal disease among hospitalized patients is invasive candidiasis. Among Candida species, C. albicans and C. glabrata rank first and second in isolation frequency, respectively, accounting for ~70% of all systemic candidiasis. This project investigates new antifungal strategies that target the BET family of transcriptional regulators in these Candida species. RATIONALE: The fungal BET protein Bdf1 contains two bromodomains (BDs) and an extra-terminal domain (ET). We recently established the proof of concept that small-molecule inhibition of Bdf1 BDs compromises the viability and virulence of C. albicans (Mietton et al., Nature Communications 2017 and patent WO2018022802A1) and C. glabrata (unpublished data). Bdf1 BD inhibitors thus hold great promise for development as a novel class of antifungal drug. In addition, preliminary data suggest that the Bdf1 ET domain may also constitute a potential therapeutic target. OBJECTIVES: Specific aims of this project are: (i) to generate Bdf1 BD inhibitors with high potency, high selectivity relative to human BDs and demonstrated antifungal activity in a mouse model of disseminated candidiasis; (ii) to validate the Bdf1 ET domain as an antifungal drug target and identify novel ET inhibitory molecules; (iii) to develop an innovative nanoparticle-based delivery strategy that enhances the potency of Bdf1 inhibitors in C. albicans and C. glabrata. NOVELTY: Small-molecule inhibitors targeting chromatin signaling pathways ("epi-drugs") have recently entered the clinic or are in clinical trials to treat cancer and other diseases. By contrast, epigenetic targets have largely remained unexplored in the fungal infection field. Thus, our investigation of Bdf1 as a therapeutic target to combat invasive candidiasis represents a novel and highly promising area of exploration in the antifungal field. BIOMEDICAL RELEVANCE: Candida species annually account for >750,000 cases of systemic infection, with a mortality rate above 40% for patients under antifungal therapy. Hospital costs for invasive candidiasis treatments are exorbitant, estimated at over 40k€ for an adult patient and 130 k€ per child. The translation of Bdf1 inhibitors into new antifungal therapies will have a substantial impact on the health of individuals at risk of an invasive fungal infection and in the long term lead to a significant reduction in national health care costs. CONSORTIUM: This project is a collaborative effort involving four French, one American and one British research groups. It mobilizes a collective expertise in genetics, medicinal chemistry, structural biology, biochemistry, nanotechnology and medical mycology.