Proteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans
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Universidade Federal de Minas Gerais
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Artigo de periódico
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Membros da banca
Resumo
The current therapeutic challenges for treating fungal diseases demand new approaches and new drugs. A promising strategy involves combination therapy with agents of distinct mechanisms of action to increase fungicidal activity and limit the impact of mutations leading to resistance. In this study, we evaluated the antifungal potential of bortezomib by examining the inhibition of proteasome activity, cell proliferation, and capsule production by Cryptococcus neoformans, the causative agent of fungal meningoencephalitis. Chemical genetic screens with collections of deletion mutants identified potential druggable targets for combination therapy with bortezomib. In vitro assays of combinations of bortezomib with flucytosine, chlorpromazine, bafilomycin A1, copper sulfate, or hydroxyurea revealed antifungal effects against C. neoformans. Furthermore, combination treatment with bortezomib and flucytosine in a murine inhalation model of cryptococcosis resulted in the improvement of neurological functions and reduced fungal replication and dissemination, leading to a delay in disease progression. This study therefore highlights the utility of chemical genetic screens to identify new therapeutic approaches as well as the antifungal potential of proteasome inhibition.
Abstract
Assunto
Microbiologia, Fungos
Palavras-chave
Bortezomib, Chemical genetic screen, Fungal pathogenesis, HIV/AIDS
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https://journals.asm.org/doi/epdf/10.1128/spectrum.01904-23