In Vitro Activity of Calcineurin and Heat Shock Protein 90 Inhibitors against Aspergillus fumigatus Azole- and Echinocandin-Resistant Strains
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Due to the limited number of antifungals and the emergence of resistance, new therapies against invasive aspergillosis are needed. We show that calcineurin inhibitors are active in vitro against both azole- and echinocandin-resistant Aspergillus fumigatus strains. The heat shock protein 90 (Hsp90) inhibitor geldanamycin had modest activity when used alone, but its combination with caspofungin or tacrolimus (FK506) resulted in fungicidal activity against azole-resistant strains. Targeting the Hsp90-calcineurin axis is a promising alternative strategy against azole-resistant A. fumigatus strains.
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Calcineurin inhibitors (FK506 and cyclosporine) and Hsp90 inhibitors (geldanamycin, 17-AAG, and 17-DMAG) are active against A. fumigatus and potentiate the effect of caspofungin.
“Calcineurin inhibitors (FK506 and cyclosporine) and Hsp90 inhibitors (geldanamycin, 17-allylamino-17-demethoxygeldanamycin [17-AAG], and 17-demethylaminoethylamino-17-demethoxygeldanamycin [17-DMAG]) are active against A. fumigatus and potentiate the effect of caspofungin (6–8)”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [8]
The impact of Hsp90 on drug resistance is conserved in other fungal pathogens, including Candida glabrata and Aspergillus fumigatus.
“Moreover, the impact of Hsp90 on drug resistance has been conserved in a number of other fungal pathogens, including Candida glabrata and Aspergillus fumigatus (12–14).”
From Genetic Analysis of <i>Candida auris</i> Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance (2019) · cites this paper as [14]
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Linking calcium signaling and mitochondrial function in fungal drug resistance
Bowyer, P., Bromley, M., & Denning, D. W. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1920497117 · Cited by 8 · see citing works
Therapeutic Approaches for Combating Aspergillus Associated Infection
Chhillar, A. K., Punia, A., Choudhary, P., Sharma, N., Dahiya, S., & Gulia, P. (2022) · Current Drug Targets · doi:10.2174/1389450123666220623164548 · Cited by 7 · see citing works
Insights into the role of sphingolipids in antifungal drug resistance
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In vitro interactions between 17‐ AAG and azoles against Exophiala dermatitidis
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Extracellular fungal Hsp90 represents a promising therapeutic target for combating fungal infections
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The Ins and Outs of Azole Antifungal Drug Resistance: Molecular Mechanisms of Transport
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- Authors
- Lamoth, F., Juvvadi, P. R., Gehrke, C., & Steinbach, W. J.
- Affiliations
- Duke Medical Center (US)
- Duke University (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2013-02
- Volume
- 57
- Issue
- 2
- Pages
- 1035-1039
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3553695
- OpenAlex
- W2120004156
- Cited by
- 88
- References
- 27
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 7 · 2018: 5 · 2017: 8 · 2016: 9 · 2015: 8 · 2014: 12 · 2013: 6
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (142746)
- Ministerio de Economía y Competitividad
- National Institute of Allergy and Infectious Diseases (R56AI077648)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Aspergillus fumigatus, calcineurin inhibitors, Hsp90 inhibitors, geldanamycin, tacrolimus, caspofungin, azole resistance, echinocandin resistance, invasive aspergillosis, antifungal resistance, combination therapy, fungicidal activity
- MeSH terms
- Caspofungin, Antifungal Agents, Aspergillosis, Aspergillus fumigatus, Azoles, Drug Therapy, Combination, Microbial Sensitivity Tests, Benzoquinones, Tacrolimus, HSP90 Heat-Shock Proteins, Drug Resistance, Multiple, Fungal, Lactams, Macrocyclic, Echinocandins, Lipopeptides, Calcineurin Inhibitors
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