Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen

The increasing prevalence of antifungal resistance represents a major clinical challenge. To explore potential new therapeutic avenues, we investigated fitness trade-offs associated with azole and echinocandin resistance in Nakaseomyces glabratus (syn. Candida glabrata), a priority yeast pathogen sh...

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Autores: Núñez Rodríguez, Juan Carlos, Schikora Tamarit, Miquel Àngel, Gabaldón Esteban, Toni
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2026
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:dnet:recercat____::6f99417149b016ddfecd5d299a176007
Acceso en línea:https://hdl.handle.net/2445/229235
Access Level:acceso abierto
Palabra clave:Medicaments antifúngics
Resistència als medicaments
Antifungal agents
Drug resistance
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spelling Uncovering actionable trade-offs of antifungal resistance in a yeast pathogenNúñez Rodríguez, Juan CarlosSchikora Tamarit, Miquel ÀngelGabaldón Esteban, ToniMedicaments antifúngicsResistència als medicamentsAntifungal agentsDrug resistanceThe increasing prevalence of antifungal resistance represents a major clinical challenge. To explore potential new therapeutic avenues, we investigated fitness trade-offs associated with azole and echinocandin resistance in Nakaseomyces glabratus (syn. Candida glabrata), a priority yeast pathogen showing growing incidence of drug and multidrug resistance. For this, we comprehensively phenotyped a large collection (n = 77) of azole- and echinocandin-resistant strains to uncover resistance-associated stress sensitivity trade-offs. Our results show that increased stress sensitivity is a common trade-off of drug resistance in this species, with 98% of resistant strains exhibiting reduced fitness under at least one of six assayed stresses. Despite the diversity of genetic backgrounds and resistance mechanisms represented by our collection, we identified consistent trends in some resistance-associated vulnerabilities. Using multivariate modeling we uncovered complex genetic interactions underlying these trade-offs. As a proof of concept for therapeutic potential, we experimentally validated the inhibitory effects of targeting some fitness trade-offs. Cyclosporin A selectively inhibited anidulafungin-resistant strains, while NaCl effectively suppressed the emergence of fluconazole resistance. This study highlights the widespread occurrence of fitness costs associated with antifungal resistance and emphasizes their potential as a novel therapeutic strategy against this growing threat.Springer2026202620262026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion26application/pdfhttps://hdl.handle.net/2445/229235Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1038/s44320-025-00185-3Molecular Systems Biology, 2026, vol. 22, num. 4, pp. 537-562https://doi.org/10.1038/s44320-025-00185-3cc by (c) Núñez Rodríguez, Juan Carlos et al., 2026https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:dnet:recercat____::6f99417149b016ddfecd5d299a1760072026-05-29T05:05:01Z
dc.title.none.fl_str_mv Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
title Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
spellingShingle Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
Núñez Rodríguez, Juan Carlos
Medicaments antifúngics
Resistència als medicaments
Antifungal agents
Drug resistance
title_short Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
title_full Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
title_fullStr Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
title_full_unstemmed Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
title_sort Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
dc.creator.none.fl_str_mv Núñez Rodríguez, Juan Carlos
Schikora Tamarit, Miquel Àngel
Gabaldón Esteban, Toni
author Núñez Rodríguez, Juan Carlos
author_facet Núñez Rodríguez, Juan Carlos
Schikora Tamarit, Miquel Àngel
Gabaldón Esteban, Toni
author_role author
author2 Schikora Tamarit, Miquel Àngel
Gabaldón Esteban, Toni
author2_role author
author
dc.subject.none.fl_str_mv Medicaments antifúngics
Resistència als medicaments
Antifungal agents
Drug resistance
topic Medicaments antifúngics
Resistència als medicaments
Antifungal agents
Drug resistance
description The increasing prevalence of antifungal resistance represents a major clinical challenge. To explore potential new therapeutic avenues, we investigated fitness trade-offs associated with azole and echinocandin resistance in Nakaseomyces glabratus (syn. Candida glabrata), a priority yeast pathogen showing growing incidence of drug and multidrug resistance. For this, we comprehensively phenotyped a large collection (n = 77) of azole- and echinocandin-resistant strains to uncover resistance-associated stress sensitivity trade-offs. Our results show that increased stress sensitivity is a common trade-off of drug resistance in this species, with 98% of resistant strains exhibiting reduced fitness under at least one of six assayed stresses. Despite the diversity of genetic backgrounds and resistance mechanisms represented by our collection, we identified consistent trends in some resistance-associated vulnerabilities. Using multivariate modeling we uncovered complex genetic interactions underlying these trade-offs. As a proof of concept for therapeutic potential, we experimentally validated the inhibitory effects of targeting some fitness trade-offs. Cyclosporin A selectively inhibited anidulafungin-resistant strains, while NaCl effectively suppressed the emergence of fluconazole resistance. This study highlights the widespread occurrence of fitness costs associated with antifungal resistance and emphasizes their potential as a novel therapeutic strategy against this growing threat.
publishDate 2026
dc.date.none.fl_str_mv 2026
2026
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/229235
url https://hdl.handle.net/2445/229235
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s44320-025-00185-3
Molecular Systems Biology, 2026, vol. 22, num. 4, pp. 537-562
https://doi.org/10.1038/s44320-025-00185-3
dc.rights.none.fl_str_mv cc by (c) Núñez Rodríguez, Juan Carlos et al., 2026
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Núñez Rodríguez, Juan Carlos et al., 2026
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 26
application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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