Restoring sensitivity to azoles in candidemia – RESTOR

Fungi infect a billion people, 3 million invasively and 1.5 million deadly. Candida species are the most involved in humans against which antifungal drugs have been developed, among which azoles are the most widely used. Candida triggers a resistance to azole by expressing Cdr1, a membrane pump that reject those toxic drugs.
Targeting Cdr1 looks as a promising combination-therapy strategy for which, however, its application in antifungal treatment is only being explored. RESTOR will give means to fill this gap.
Such strategy needs structure-target information to know how Cdr1 works and to rationally design inhibitors. We got such data by resolving cryo-EM structures of Cdr1 in various states. We also synthesized a series of ‘LG’ ligands and resolved the cryo-EM structure of one of them, ‘LG03’, bound to drug-binding pocket (DBP).
This unique data make us confident to reach our goal, by developing 3 work packages: 1°/ Acquisition of additional key-information of the molecular mechanism of Cdr1 by resolving cryo-EM structures of a couple of mutants invalidating transport and corresponding revertants re-allowing it that we have characterized, 2°/ In-silico optimization, syntheses and biological tests of LG03 derivatives to generate Cdr1 inhibitors re-sensitizing azole-resistant yeast, 3°/ Vast in-silico screening of the ZINC chemolibrary to identify other potential drugs binging to the DBP and also to the extra-cellular domain of cgCdr1, accessible from outside the yeast. Our ambition is to obtain a drug that restores the sensitivity of yeasts to azole antifungals, enabling their therapeutic development.
RESTOR will be carried out by 2 partners with complementary expertise in Structural Biochemistry and Medicinal Chemistry based on 15 years of fruitful collaboration having led to high impact factor publications (Angewandte Chem. 2018; Science Advances, 2022), 4 licensed patents and the creation of 2 startups.