title: Antifungal application of nonantifungal drugs.
abstract: Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ∼150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis.
authors.affiliation: Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
authors.forename: Marios
authors.initials: M
authors.lastname: Stylianou
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kulesskiy
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Lopes
authors.forename: Margareta
authors.initials: M
authors.lastname: Granlund
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.forename: Constantin F
authors.initials: CF
authors.lastname: Urban
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002175:Candida / Q000187:drug effects* / Q000254:growth & development; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D058492:Drug Repositioning; D025141:Drug Resistance, Fungal; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D054852:Small Molecule Libraries; C531970:tosedostat; D005998:Glycine