Antifungal Activity of Compounds Targeting the Hsp90‐Calcineurin Pathway Against Various Mould Species
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Objectives: Invasive mould infections are associated with a high mortality rate and the emergence of MDR moulds is of particular concern. Calcineurin and its chaperone, the heat shock protein 90 (Hsp90), represent an important pathway for fungal virulence that can be targeted at different levels. We investigated the antifungal activity of compounds directly or indirectly targeting the Hsp90-calcineurin axis against different mould species. Methods: The in vitro antifungal activity of the anticalcineurin drug FK506 (tacrolimus), the Hsp90 inhibitor geldanamycin, the lysine deacetylase inhibitor trichostatin A and the Hsp70 inhibitor pifithrin-μ was assessed by the standard broth dilution method against 62 clinical isolates of Aspergillus spp. and non-Aspergillus moulds (Mucoromycotina, Fusarium spp., Scedosporium spp., Purpureocillium/Paecilomyces spp. and Scopulariopsis spp.) Results: FK506 had variable antifungal activity against different Aspergillus spp. and was particularly active against Mucor spp. Geldanamycin had moderate antifungal activity against Fusarium spp. and Paecilomyces variotii. Importantly, trichostatin A had good activity against the triazole-resistant Aspergillus ustus and the amphotericin B-resistant Aspergillus terreus as well as the MDR Scedosporium prolificans. Moreover, trichostatin A exhibited synergistic interactions with caspofungin against A. ustus and with geldanamycin against Rhizopus spp. for which none of the other agents showed activity. Pifithrin-μ exhibited little antifungal activity. Conclusions: Targeting the Hsp90-calcineurin axis at different levels resulted in distinct patterns of susceptibility among different fungal species. Lysine deacetylase inhibition may represent a promising novel antifungal strategy against emerging resistant moulds.
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The primary HR mechanism in C. glabrata distinguishes itself from models in C. albicans and C. neoformans, where aneuploidy is a common driver.
“Mechanistically, the primary HR mechanism in C. glabrata distinguishes itself from models in C. albicans and C. neoformans, where aneuploidy is a common driver [27, 42, 43].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [27]
The Introduction (p. 1) and Discussion (p. 3) address antifungal activity against moulds, not heteroresistance mechanisms in the three named species. Searches for C. glabrata, C. albicans, C. neoformans, aneuploidy, and heteroresistance found no passage addressing the comparison. (LLM, conf=0.76)
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References 22 · Cited by 47
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- 5 Iwen PC, Schutte SD, Florescu DF et al . Invasive Scopulariopsis brevicaulis infection in an immunocompromised patient and review of prior cases caused by Scopulariopsis and Microascus species. Med Mycol 2012; 50 : 561-9.
- Fungi-Second Edition: Approved Standard M38-A2 . CLSI, Wayne, PA, USA, 2008.
- Authors
- Lamoth, F., Alexander, B. D., Juvvadi, P. R., & Steinbach, W. J.
- Affiliations
- Duke University (US)
- Corresponding author
- Lamoth, Frédéric
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-01-03
- Volume
- 70
- Issue
- 5
- Pages
- 1408-1411
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- OpenAlex
- W2014461010
- Cited by
- 47
- References
- 22
- Citations by year
- 2026: 2 · 2025: 4 · 2023: 3 · 2022: 8 · 2021: 4 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 2
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- reroDoc Digital Library (submittedVersion)
- IRIS (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (151742)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- antifungal activity, mold infections, Aspergillus, Fusarium, Scedosporium, Mucoromycotina, FK506, tacrolimus, geldanamycin, trichostatin A, pifithrin-μ, HSP70 inhibition, triazole resistance, amphotericin B resistance, Rhizopus, Paecilomyces variotii, Scopulariopsis
- MeSH terms
- Antifungal Agents, Enzyme Inhibitors, Fungi, Microbial Sensitivity Tests, HSP90 Heat-Shock Proteins, Calcineurin
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