Proteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans

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dc.creatorMélissa Caza
dc.creatorDaniel Assis Santos
dc.creatorElizabeth Burden
dc.creatorAnna Brisland
dc.creatorGuanggan Hu
dc.creatorJames W. Kronstad
dc.date.accessioned2025-01-21T21:41:50Z
dc.date.accessioned2025-09-09T00:44:51Z
dc.date.available2025-01-21T21:41:50Z
dc.date.issued2023-10-17
dc.format.mimetypepdf
dc.identifier.doihttps://doi.org/10.1128/spectrum.01904-23
dc.identifier.issn2165-0497
dc.identifier.urihttps://hdl.handle.net/1843/79388
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofMicrobiology Spectrum
dc.rightsAcesso Aberto
dc.subjectMicrobiologia
dc.subjectFungos
dc.subject.otherBortezomib
dc.subject.otherChemical genetic screen
dc.subject.otherFungal pathogenesis
dc.subject.otherHIV/AIDS
dc.titleProteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans
dc.typeArtigo de periódico
local.citation.epage17
local.citation.issue5
local.citation.spage1
local.citation.volume11
local.description.resumoThe 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.
local.identifier.orcidhttps://orcid.org/0000-0002-5403-8034
local.identifier.orcidhttps://orcid.org/0000-0002-1108-5666
local.identifier.orcidhttps://orcid.org/0000-0002-2274-0312
local.identifier.orcidhttps://orcid.org/0000-0003-4240-6976
local.publisher.countryBrasil
local.publisher.departmentICB - DEPARTAMENTO DE MICROBIOLOGIA
local.publisher.initialsUFMG
local.url.externahttps://journals.asm.org/doi/epdf/10.1128/spectrum.01904-23

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