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. 2014;58(2):1055-62.
doi: 10.1128/AAC.01087-13. Epub 2013 Nov 25.

Antifungal application of nonantifungal drugs

Marios Stylianou  1 , Evgeny Kulesskiy, José Pedro Lopes, Margareta Granlund, Krister Wennerberg, Constantin F Urban
Affiliations

Antifungal application of nonantifungal drugs

Marios Stylianou et al. Antimicrob Agents Chemother. 2014.

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.

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Figures

FIG 1
FIG 1
C. albicans SC5314 challenged for 6 h with novel and control drugs. The pictures are taken from an IncuCyte microscope with a 20× objective lens; the scale bar corresponds to 200 μm. The drug solvent DMSO (A) and the antiseptic BzCl (B) correspond to the 100% and 0% growth controls, respectively. Fluconazole (C) and rapamycin (D) are representative control drugs. Representative images from C. albicans SC5314 were treated with haloperidol (E), trifluperidol (G), tosedostat (F), and amonafide (H). Morphological changes in C. albicans upon treatment with haloperidol (E) and trifluperidol (G) resembled those caused by fluconazole (C), whereas morphological changes in C. albicans upon treatment with tosedostat (F) and amonafide (H) resembled those of rapamycin (D).
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