Adaptive morphological changes link to poor clinical outcomes by conferring echinocandin tolerance in Candida tropicalis
Open accessAbstract
Antibiotic tolerance, by which susceptible bacteria survive at high bactericide doses, is known to cause treatment failure in clinical practice. However, the impact of antifungal tolerance on clinical outcomes remains poorly understood. Here, we observed that candidemia cases caused by echinocandin-tolerant Candida tropicalis exhibited higher mortality rates during caspofungin treatment by conducting a comprehensive seven-year retrospective analysis. C. tropicalis develops tolerance to caspofungin by forming multicellular aggregates, a process linked to defects in cell division, both in vitro and in vivo. Our omics-based profiling results reveal that C. tropicalis develops tolerance through the intricate modulation of cell wall integrity and cell division pathways, particularly through the activation of chitin synthesis and the downregulation of cell division-related genes. The overexpression of cell division-related factor Ace2 can suppress the tolerance of C. tropicalis to caspofungin by delaying the formation of multicellular aggregates. Moreover, calcineurin inhibitors can suppress the tolerance of C. tropicalis by disrupting these adaptive molecular changes, thereby significantly enhancing the antifungal efficacy of caspofungin in a Galleria mellonella model. Collectively, our findings provide evidence that C. tropicalis acquires echinocandin tolerance through morphological alterations, and that inhibiting calcineurin may be a promising method to reduce this tolerance.
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Fungi primarily rely on the Cell Wall Integrity and Calcineurin signaling pathways for survival in response to cell wall stress induced by drugs like caspofungin.
“In response to cell wall stress induced by drugs like caspofungin, fungi primarily rely on the Cell Wall Integrity and Calcineurin signaling pathways for survival [14, 15, 16].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [14]
The Introduction (page not provided) says caspofungin induces cell-wall stress responses regulated by calcineurin, Hsp90, and MAPK pathways. The Discussion (page not provided) links calcineurin to cell-wall integrity and reports that calcineurin inhibitors suppress survival-related adaptations in tolerant C. tropicalis strains. The paper does not establish that fungi broadly rely primarily on the two named pathways for survival. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCalcineurin is a critical mediator of fungal cell wall stress responses and survival under antifungal pressure.
“The latter one, a highly conserved calcium/calmodulin‐dependent signaling cascade [17], is a critical mediator of fungal cell wall stress responses and survival under antifungal pressure [14, 18].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [14]
FK506 abolished the tolerance of C. tropicalis and substantially increased the lifespan of infected animals undergoing echinocandin treatment.
“Though the molecular mechanisms of echinocandin heteroresistance and tolerance have not been elucidated, an inhibitor of the Ca2+/calmodulin-dependent protein phosphatase calcineurin (FK506) abolished the tolerance of C. tropicalis and substantially increased the lifespan of infected animals undergoing echinocandin treatment (14).”
From Echinocandin tolerance and persistence <i>in vitro</i> are regulated by calcineurin signaling in <i>Candida glabrata</i> (2026) · cites this paper as [14]
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“The latter one, a highly conserved calcium/calmodulin-dependent signaling cascade [ 17 ], is a critical mediator of fungal cell wall stress responses and survival under antifungal pressure [ 14, 18 ].”
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Self-citation
- Authors
- Wu, Y., Zou, Y., Dai, Y., Lu, H., Zhang, W., Chang, W., Wang, Y., Nie, Z., Wang, Y., & Jiang, X.
- Affiliations
- University of Science and Technology of China (CN)
- Chinese Academy of Sciences (CN)
- Anhui Provincial Center for Disease Control and Prevention (CN)
- Corresponding author
- Wu, Yongqin
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2025-05-27
- Volume
- 21
- Issue
- 5
- Pages
- e1013220
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC12140413
- OpenAlex
- W4410769837
- Cited by
- 10
- References
- 43
- Citations by year
- 2026: 8 · 2025: 2
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Update notices
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82102454)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida tropicalis, caspofungin, candidemia, multicellular aggregates, cell division defects, cell wall integrity, chitin synthesis, ACE2, calcineurin inhibitors, antifungal resistance, Galleria mellonella model, clinical outcomes
- MeSH terms
- Caspofungin, Animals, Antifungal Agents, Candidiasis, Humans, Microbial Sensitivity Tests, Retrospective Studies, Drug Resistance, Fungal, Candida tropicalis, Echinocandins, Candidemia
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