title: Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole.
abstract: Resistance to widely used fungistatic drugs, particularly to the ergosterol biosynthesis inhibitor fluconazole, threatens millions of immunocompromised patients susceptible to invasive fungal infections. The dense network structure of synthetic lethal genetic interactions in yeast suggests that combinatorial network inhibition may afford increased drug efficacy and specificity. We carried out systematic screens with a bioactive library enriched for off-patent drugs to identify compounds that potentiate fluconazole action in pathogenic Candida and Cryptococcus strains and the model yeast Saccharomyces. Many compounds exhibited species- or genus-specific synergism, and often improved fluconazole from fungistatic to fungicidal activity. Mode of action studies revealed two classes of synergistic compound, which either perturbed membrane permeability or inhibited sphingolipid biosynthesis. Synergistic drug interactions were rationalized by global genetic interaction networks and, notably, higher order drug combinations further potentiated the activity of fluconazole. Synergistic combinations were active against fluconazole-resistant clinical isolates and an in vivo model of Cryptococcus infection. The systematic repurposing of approved drugs against a spectrum of pathogens thus identifies network vulnerabilities that may be exploited to increase the activity and repertoire of antifungal agents.
authors.affiliation: Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Michaela
authors.initials: M
authors.lastname: Spitzer
authors.forename: Emma
authors.initials: E
authors.lastname: Griffiths
authors.forename: Kim M
authors.initials: KM
authors.lastname: Blakely
authors.forename: Jan
authors.initials: J
authors.lastname: Wildenhain
authors.forename: Linda
authors.initials: L
authors.lastname: Ejim
authors.forename: Laura
authors.initials: L
authors.lastname: Rossi
authors.forename: Gianfranco
authors.initials: G
authors.lastname: De Pascale
authors.forename: Jasna
authors.initials: J
authors.lastname: Curak
authors.forename: Eric
authors.initials: E
authors.lastname: Brown
authors.forename: Mike
authors.initials: M
authors.lastname: Tyers
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects* / Q000254:growth & development; D019295:Computational Biology; D003454:Cryptococcus / Q000187:drug effects* / Q000254:growth & development; D025141:Drug Resistance, Fungal / Q000235:genetics; D004357:Drug Synergism; D004875:Ergosterol / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015725:Fluconazole / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods; D007313:Insecta / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D012440:Saccharomyces / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D013045:Species Specificity
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole; D004875:Ergosterol