Candida's Hidden Weakness: Characterising Novel Hsp90 Interactions to Discover New Drug Targets in Candidaemia

Heat shock protein 90 (Hsp90) is a chaperone protein in eukaryotes and bacteria that stabilises proteins during environmental stress and acts as a major protein interaction hub. In the human pathogen Candida albicans, Hsp90 controls virulence and drug resistance through its interactions with 5% of the genome. C. albicans and its relative, C. glabrata, cause ~75% of invasive Candida infections (candidaemia). For severely immunocompromised patients, mortality rates for candidaemia exceed 50% and over 50,000 deaths are attributed to it globally every year. Few drugs are available to treat Candida infections and resistance to these is growing, compounded by C. glabrata's intrinsic resistance to azoles. Due to conservation between orthologues, current medicines targeting Hsp90 are too toxic to use at anti-fungal doses, however it is hoped that Hsp90 interactors may be less conserved and be better drug targets. Therefore, this project investigates genetic and physical interactors of Hsp90 in C. albicans and C. glabrata.
In C. albicans 5 kinases that interact with Hsp90 also influence virulence and drug resistance. Direct interactions between these 5 kinases and Hsp90 will be further characterised using in vitro biochemistry and electron cryo-microscopy, providing structural information for rational drug design. In C. glabrata a knock-out library covering 15% of the genome will be screened for genetic interactors with Hsp90. To date, screening ~5% of the C. glabrata genome has identified 15 putative interactors. Together, these data provide new information about Hsp90 interactors in pathogenic Candida species, which may be further developed as novel anti-fungal drug target.s