Calcineurin activity in Fonsecaea pedrosoi: tacrolimus and cyclosporine A inhibited conidia growth, filamentation and showed synergism with itraconazole.

Autor: Sousa IS; Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos (LTBBF), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, 21040-900, Brazil., Tavares LFS; Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos (LTBBF), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, 21040-900, Brazil., Silva BA; Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, 21941-901, Brazil., Moreno DSA; Laboratório de Estrutura de Microrganismos, IMPG, UFRJ, Rio de Janeiro, 21941-902, Brazil., Alviano CS; Laboratório de Estrutura de Microrganismos, IMPG, UFRJ, Rio de Janeiro, 21941-902, Brazil., Santos ALS; Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, 21941-901, Brazil.; Rede Micologia RJ, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro, 21941-901, Brazil., Kneipp LF; Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos (LTBBF), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, 21040-900, Brazil. lucimar@ioc.fiocruz.br.; Rede Micologia RJ, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro, 21941-901, Brazil. lucimar@ioc.fiocruz.br.
Jazyk: angličtina
Zdroj: Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] [Braz J Microbiol] 2024 Jul 24. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1007/s42770-024-01463-2
Abstrakt: Fonsecaea pedrosoi is a melanized fungus that causes chromoblastomycosis (CBM), a tropical neglected disease responsible for chronic and disability-related subcutaneous mycosis. Given the challenging nature of CBM treatment, the study of new targets and novel bioactive drugs capable of improving patient life quality is urgent. In the present work, we detected a calcineurin activity in F. pedrosoi conidial form, employing primarily colorimetric, immunoblotting and flow cytometry assays. Our findings reveal that the calcineurin activity of F. pedrosoi was stimulated by Ca 2+ /calmodulin, inhibited by EGTA and specific inhibitors, such as tacrolimus (FK506) and cyclosporine A (CsA), and proved to be insensitive to okadaic acid. In addition, FK506 and CsA were able to affect the cellular viability and the fungal proliferation. This effect was corroborated by transmission electron microscopy that showed both calcineurin inhibitors promoted profound changes in the ultrastructure of conidia, causing mainly cytoplasm condensation and intense vacuolization that are clear indication of cell death. Our data indicated that FK506 exhibited the highest effectiveness, with a minimum inhibitory concentration (MIC) of 3.12 mg/L, whereas CsA required 15.6 mg/L to inhibit 100% of conidial growth. Interestingly, when both were combined with itraconazole, they demonstrated anti-F. pedrosoi activity, exhibiting a synergistic effect. Moreover, the fungal filamentation was affected after treatment with both calcineurin inhibitors. These data corroborate with other calcineurin studies in fungal cells and open up further discussions aiming to establish the role of this enzyme as a potential target for antifungal therapy against CBM infections.
(© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)
Databáze: MEDLINE
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