title: Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease.
abstract: Invasive fungal infections are a leading cause of mortality among immunocompromised individuals. Treatment is notoriously difficult with the limited armamentarium of antifungal drugs, whose efficacy is compromised by host toxicity, a limited activity spectrum, or the emergence of drug resistance. We previously established that the molecular chaperone Hsp90 enables the emergence and maintenance of fungal drug resistance. For the most prevalent fungal pathogen of humans, Candida albicans, Hsp90 mediates resistance to azoles, which inhibit ergosterol biosynthesis and are the most widely deployed antifungals in the clinic. For the emerging opportunistic pathogen Aspergillus terreus, Hsp90 is required for basal resistance to echinocandins, which inhibit beta(1, 3)-glucan synthesis and are the only new class of antifungals to reach the clinic in decades. Here, we explore the therapeutic potential of Hsp90 inhibitors in fungal disease using a tractable host-model system, larvae of the greater wax moth Galleria mellonella, and a murine model of disseminated disease. Combination therapy with Hsp90 inhibitors that are well tolerated in humans and an azole rescued larvae from lethal C. albicans infections. Combination therapy with an Hsp90 inhibitor and an echinocandin rescued larvae from infections with the most lethal mold, Aspergillus fumigatus. In a murine model of disseminated candidiasis, genetic compromise of C. albicans HSP90 expression enhanced the therapeutic efficacy of an azole. Thus, harnessing Hsp90 provides a much-needed strategy for improving the treatment of fungal disease because it enhances the efficacy of existing antifungals, blocks the emergence of drug resistance, and exerts broad-spectrum activity against diverse fungal pathogens.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. leah.cowen@utoronto.ca
authors.forename: Leah E
authors.initials: LE
authors.lastname: Cowen
authors.forename: Sheena D
authors.initials: SD
authors.lastname: Singh
authors.forename: Julia R
authors.initials: JR
authors.lastname: Köhler
authors.forename: Cathy
authors.initials: C
authors.lastname: Collins
authors.forename: Aimee K
authors.initials: AK
authors.lastname: Zaas
authors.forename: Wiley A
authors.initials: WA
authors.lastname: Schell
authors.forename: Hamza
authors.initials: H
authors.lastname: Aziz
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Mylonakis
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use; D005658:Fungi / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology / Q000628:therapy*
chemical_list: D000935:Antifungal Agents; D018841:HSP90 Heat-Shock Proteins; D015725:Fluconazole