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Repurposing the thrombopoietin receptor agonist eltrombopag as an anticryptococcal agent.
- Source :
-
Medical mycology [Med Mycol] 2020 Jun 01; Vol. 58 (4), pp. 493-504. - Publication Year :
- 2020
-
Abstract
- In this study, a Food and Drug Administration (FDA)-approved drug with previously unreported antifungal activity was investigated for suitability for use as an anticryptococcal agent. First, we screened a compound library of 1018 FDA-approved drugs against Cryptococcus neoformans. Of 52 drugs possessing anti-Cryptococcus activity, eltrombopag was chosen due to its novel activity. The susceptibility of Cryptococcus against eltrombopag was then studied by determining the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC), while the synergy of eltrombopag with other drugs was tested by fractional inhibitory concentration index (FICI). Eltrombopag had a limited spectrum of antifungal activity against C. neoformans/C. gattii species complex (MICs of 0.125 mg/l), Candida glabrata (MIC, 0.25 mg/l), and Trichophyton rubrum (MIC, 0.5 mg/l). Eltrombopag affected cryptococcal virulence factors, including capsule and biofilm formation, melanin production, and growth ability at 37°C. Further, RNA sequencing and deletion mutant library screening experiments revealed that genes involved in the calcineurin pathway, lipid biosynthesis, membrane component, and transporter genes were associated with eltrombopag. In addition, eltrombopag showed synergism with the calcineurin inhibitor FK506 (FICI < 0.5) against Cryptococcus species. In conclusion, eltrombopag exhibited excellent antifungal activity against Cryptococcus species potentially via a mode of action which interferes with virulence factors and the calcineurin pathway, indicating that eltrombopag might be usefully repurposed as an antifungal agent for treating cryptococcosis.<br /> (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)
- Subjects :
- Arthrodermataceae drug effects
Biofilms drug effects
Candida glabrata drug effects
Cryptococcus classification
Cryptococcus pathogenicity
Cryptococcus gattii drug effects
Cryptococcus gattii pathogenicity
Cryptococcus neoformans drug effects
Cryptococcus neoformans pathogenicity
Drug Synergism
Metabolic Networks and Pathways
Microbial Sensitivity Tests
Receptors, Thrombopoietin agonists
Small Molecule Libraries
Tacrolimus pharmacology
Antifungal Agents pharmacology
Benzoates pharmacology
Cryptococcus drug effects
Drug Repositioning
Hydrazines pharmacology
Pyrazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2709
- Volume :
- 58
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Medical mycology
- Publication Type :
- Academic Journal
- Accession number :
- 31297540
- Full Text :
- https://doi.org/10.1093/mmy/myz077