Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 03 2023
02 03 2023
Historique:
received:
14
10
2022
accepted:
22
02
2023
entrez:
2
3
2023
pubmed:
3
3
2023
medline:
7
3
2023
Statut:
epublish
Résumé
Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.
Identifiants
pubmed: 36864040
doi: 10.1038/s41467-023-36882-6
pii: 10.1038/s41467-023-36882-6
pmc: PMC9981703
doi:
Substances chimiques
Antifungal Agents
0
Echinocandins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1183Subventions
Organisme : NIAID NIH HHS
ID : R01 AI109025
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA051008
Pays : United States
Informations de copyright
© 2023. The Author(s).
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