Calcineurin Inhibitor CN585 Exhibits Off-Target Effects in the Human Fungal Pathogen Aspergillus fumigatus

Calcineurin (CN) is an attractive antifungal target as it is critical for growth, stress response, drug resistance, and virulence in fungal pathogens. The immunosuppressive drugs, tacrolimus (FK506) and cyclosporin A (CsA), are fungistatic and specifically inhibit CN through binding to their respect...

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Bibliographic Details
Published in:Journal of fungi (Basel) 2022-12, Vol.8 (12), p.1281
Main Authors: Juvvadi, Praveen R, Bobay, Benjamin G, Cole, D Christopher, Awwa, Monaf, Steinbach, William J
Format: Article
Language:English
Subjects:
Aspergillosis
Aspergillus
Aspergillus fumigatus
Calcineurin
Calcineurin inhibitors
CN585
Crystal structure
cyclophilin
Cyclosporin A
Digital cameras
Drug resistance
Echinocandins
FK506
Immunophilins
Immunosuppressive agents
Microscopy
Nuclear transport
Pathogens
Proteins
Resistant mutant
Simulation
Tacrolimus
Tacrolimus-binding protein
Virulence
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Summary:Calcineurin (CN) is an attractive antifungal target as it is critical for growth, stress response, drug resistance, and virulence in fungal pathogens. The immunosuppressive drugs, tacrolimus (FK506) and cyclosporin A (CsA), are fungistatic and specifically inhibit CN through binding to their respective immunophilins, FK506-binding protein (FKBP12), and cyclophilin (CypA). We are focused on CN structure-based approaches for the development of non-immunosuppressive FK506 analogs as antifungal therapeutics. Here, we examined the effect of the novel CN inhibitor, CN585, on the growth of the human pathogen , the most common cause of invasive aspergillosis. Unexpectedly, in contrast to FK506, CN585 exhibited off-target effect on wild-type and the azole- and echinocandin-resistant strains. Unlike with FK506 and CsA, the CN, FKBP12, CypA mutants (Δ , Δ , Δ ) and various FK506-resistant mutants were all sensitive to CN585. Furthermore, in contrast to FK506 the cytosolic to nuclear translocation of the CN-dependent transcription factor (CrzA-GFP) was not inhibited by CN585. Molecular docking of CN585 onto human and CN complexes revealed differential potential binding sites between human CN versus CN. Our results indicate CN585 may be a non-specific inhibitor of CN with a yet undefined antifungal mechanism of activity.
ISSN:2309-608X
2309-608X
DOI:10.3390/jof8121281