Outbreaks of fluconazole-resistant Candida parapsilosis are driven by low-biofilm-producing isolates that emerge under host selection

Candida parapsilosis is a major human fungal pathogen, with recent global outbreaks driven by fluconazole-resistant (FLCR-Cp) isolates that are difficult to eradicate and associated with poor clinical outcomes. However, the microbial traits enabling persistence of these outbreak lineages remain poorly defined. Here, we show that FLCR-Cp isolates responsible for prolonged, multi-country outbreaks consistently exhibit a striking low-biofilm-producing (LBP) phenotype. Contrary to the prevailing view that robust biofilm formation promotes persistence, LBP strains displayed enhanced stress tolerance, increased cell wall masking, and reduced immune recognition. These traits conferred resistance to neutrophil and macrophage killing and enhanced survival in immune cell-rich organs during systemic infection. Genome-wide transcriptomic profiling revealed extensive metabolic and regulatory rewiring in LBP strains. Whole-genome sequencing (WGS) of a global isolate collection further demonstrated that the LBP phenotype has emerged independently multiple times, supporting convergent evolution under host selection. Functional genomic analyses suggest that biofilm attenuation arises through multigenic changes, and disruption of key biofilm-associated transcriptional regulators enhanced fitness during immune interactions. Together, our findings overturn the assumption that robust biofilm formation drives outbreak persistence and instead identify biofilm attenuation as an adaptive tradeoff that promotes immune evasion and long-term survival. These results redefine our understanding of C. parapsilosis adaptation during healthcare-associated outbreaks and shift attention toward host-driven evolutionary processes than environmental persistence alone.

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Publication Details

Journal
PLoS Biology
Published
2026-09-01
DOI
https://doi.org/10.1371/journal.pbio.3003973
Primary Topic
Antifungal resistance and susceptibility
Type
article
Field-Weighted Citation Impact
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article

Outbreaks of fluconazole-resistant Candida parapsilosis are driven by low-biofilm-producing isolates that emerge under host selection

Toni Gabaldón, Michael K. Mansour, Farnaz Daneshnia, Geraldine Butler et al.
PLoS Biology
Antifungal resistance and susceptibility
article

Outbreaks of fluconazole-resistant Candida parapsilosis are driven by low-biofilm-producing isolates that emerge under host selection

Toni Gabaldón, Michael K. Mansour, Farnaz Daneshnia, Geraldine Butler, Clarissa J. Nobile, Oliver Kurzai, Lisa Lombardi, Jigar V. Desai, Daniel J. Floyd, Giuseppina Caggiano, Tibor Németh, Carol A. Munro, Arefeh Ebadati, Deepika Gunasekaran, Attila Gácser, Austin M. Perry, Amir Arastehfar, Shenglin Mei, Letal I. Salzberg, Agostinho Carvalho, Diego Fuentes, Gabriel Braune, Pegah Mosharaf Ghahfarokhy, João N. Almeida, Julieta Munoz, Sean Bergin, Samuel M. Gonçalves, Süleyha Hilmioglu-Polat, Alex Hopke, Tobias Köhler, Mostafa Salehi, Liuyang Cai, David S. Perlin, Louise A. Walker, Julianne V. Kus, Wenjie Fang, Relber A. Gonçales
article en

Abstract

Candida parapsilosis is a major human fungal pathogen, with recent global outbreaks driven by fluconazole-resistant (FLCR-Cp) isolates that are difficult to eradicate and associated with poor clinical outcomes. However, the microbial traits enabling persistence of these outbreak lineages remain poorly defined. Here, we show that FLCR-Cp isolates responsible for prolonged, multi-country outbreaks consistently exhibit a striking low-biofilm-producing (LBP) phenotype. Contrary to the prevailing view that robust biofilm formation promotes persistence, LBP strains displayed enhanced stress tolerance, increased cell wall masking, and reduced immune recognition. These traits conferred resistance to neutrophil and macrophage killing and enhanced survival in immune cell-rich organs during systemic infection. Genome-wide transcriptomic profiling revealed extensive metabolic and regulatory rewiring in LBP strains. Whole-genome sequencing (WGS) of a global isolate collection further demonstrated that the LBP phenotype has emerged independently multiple times, supporting convergent evolution under host selection. Functional genomic analyses suggest that biofilm attenuation arises through multigenic changes, and disruption of key biofilm-associated transcriptional regulators enhanced fitness during immune interactions. Together, our findings overturn the assumption that robust biofilm formation drives outbreak persistence and instead identify biofilm attenuation as an adaptive tradeoff that promotes immune evasion and long-term survival. These results redefine our understanding of C. parapsilosis adaptation during healthcare-associated outbreaks and shift attention toward host-driven evolutionary processes than environmental persistence alone.

PLoS BiologyVol. 24(9)
University College Dublin (IE), University of Pisa (IT), Institució Catalana de Recerca i Estudis Avançats (ES), East Tennessee State University (US), Harvard University (US), University of California, Merced (US), Georgetown University (US), University of Toronto (CA), University of Aberdeen (GB), University of Szeged (HU), University of Würzburg (DE), Georgetown University Medical Center (US), Hospital Israelita Albert Einstein (BR), Virginia–Maryland College of Veterinary Medicine (US), Ege University (TR), Massachusetts General Hospital (US), Institute of Cancer Research (CA), Institute for Biodiversity (DE), Shanghai Changzheng Hospital (CN), Centro de Investigación Biomédica en Red (ES), Institute for Research in Biomedicine (ES), Public Health Ontario (CA), Universitätsklinikum Würzburg (DE), D-Tech (United States) (US), Institute of Medical Microbiology and Hygiene (DE), Hackensack Meridian Health (US), Conway School of Landscape Design (US), Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE), Georgetown Lombardi Comprehensive Cancer Center, Institute of Medical Sciences (IN), University of Bari Aldo Moro (IT), K. N. Toosi University of Technology (IR), Virginia Tech (US), Universidade Federal de São Paulo (BR), University of Amsterdam (NL), University of Minho (PT)
National Science Foundation, Gordon and Betty Moore Foundation, Fundació la Marató de TV3, European Commission, Ministerio de Ciencia e Innovación, National Institutes of Health, Fundação para a Ciência e a Tecnologia, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Division of Materials Research
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