Critical Assessment of Cell Wall Integrity Factors Contributing to in vivo Echinocandin Tolerance and Resistance in Candida glabrata

Garcia-Rubio, Rocio; Hernandez, Rosa Y.; Clear, Alissa; Healey, Kelley R.; Shor, Erika; Perlin, David S.

doi:10.3389/fmicb.2021.702779

Cited by 35Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

Critical Assessment of Cell Wall Integrity Factors Contributing to in vivo Echinocandin Tolerance and Resistance in Candida glabrata

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Garcia-Rubio, Rocio, Hernandez, Rosa Y., Clear, Alissa, Healey, Kelley R., Shor, Erika, Perlin, David S.·2021·Frontiers in Microbiology

DOI 10.3389/fmicb.2021.702779PMC PMC8298035

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Abstract

Fungal infections are on the rise, and emergence of drug-resistant Candida strains refractory to treatment is particularly alarming. Resistance to azole class antifungals, which have been extensively used worldwide for several decades, is so high in several prevalent fungal pathogens, that another drug class, the echinocandins, is now recommended as a first line antifungal treatment. However, resistance to echinocandins is also prominent, particularly in certain species, such as Candida glabrata . The echinocandins target 1,3-β-glucan synthase (GS), the enzyme responsible for producing 1,3-β-glucans, a major component of the fungal cell wall. Although echinocandins are considered fungicidal, C. glabrata exhibits echinocandin tolerance both in vitro and in vivo , where a subset of the cells survives and facilitates the emergence of echinocandin-resistant mutants, which are responsible for clinical failure. Despite this critical role of echinocandin tolerance, its mechanisms are still not well understood. Additionally, most studies of tolerance are conducted in vitro and are thus not able to recapitulate the fungal-host interaction. In this study, we focused on the role of cell wall integrity factors in echinocandin tolerance in C. glabrata. We identified three genes involved in the maintenance of cell wall integrity – YPS1 , YPK2 , and SLT2 – that promote echinocandin tolerance both in vitro and in a mouse model of gastrointestinal (GI) colonization. In particular, we show that mice colonized with strains carrying deletions of these genes were more effectively sterilized by daily caspofungin treatment relative to mice colonized with the wild-type parental strain. Furthermore, consistent with a role of tolerant cells serving as a reservoir for generating resistant mutations, a reduction in tolerance was associated with a reduction in the emergence of resistant strains. Finally, reduced susceptibility in these strains was due both to the well described FKS -dependent mechanisms and as yet unknown, FKS -independent mechanisms. Together, these results shed light on the importance of cell wall integrity maintenance in echinocandin tolerance and emergence of resistance and lay the foundation for future studies of the factors described herein.

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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 Candida Glabrata (2026) · cites this paper as [16]
The Results (Identification of Four Candidate Genes Whose Deletions Reduce Echinocandin Tolerance; page unavailable) show that deleting several cell-wall-maintenance genes reduced Candida glabrata survival after caspofungin exposure. The paper lists CRZ1 as a calcineurin-pathway component but does not establish that fungi primarily rely on calcineurin signaling for survival. Its findings in C. glabrata also do not establish the claim for fungi generally. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Mitochondrial functions were recently implicated in ECN tolerance in C. glabrata.
“Interestingly, mitochondrial functions were recently implicated in ECN tolerance in C. glabrata (40) and were also enriched transcriptionally in CSP-treated C. auris (55).”
From Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris (2022) · cites this paper as [40]
The Results and Discussion describe cell-wall integrity genes and pathways implicated in echinocandin tolerance in C. glabrata. A search for mitochondrial functions found no passage connecting them to tolerance in our copy. (LLM, conf=0.73)
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Slt2 kinase of the cell wall integrity pathway is required for Fks2-specific echinocandin resistance in Candida glabrata
Uddin, Z., Tahsin, S., Valíčková, K., Long, T., Macedo, L. F. D., Popencuk, G., Zhao, Y., & Healey, K. R. (2026) · Microbiology Spectrum · doi:10.1128/spectrum.03874-25
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P017 Echinocandin resistance mechanism in Candida tropicalis and Candida glabrata
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Authors: Garcia-Rubio, R., Hernandez, R. Y., Clear, A., Healey, K. R., Shor, E., & Perlin, D. S.
Affiliations: Hackensack Meridian Health (US)
William Paterson University (US)
Georgetown University (US)
Corresponding author: Shor, Erika
ORCID: Healey, Kelley R.
Shor, Erika
Perlin, David S.
Venue: Frontiers in Microbiology
Publisher: Frontiers Media SA
Published: 2021-06-30
Volume: 12
Pages: 702779-702779
ISSN: 1664-302X (ISSN-L)
DOI: 10.3389/fmicb.2021.702779
PMC: PMC8298035
OpenAlex: W3177475390
Cited by: 35
References: 41
Citations by year: 2026: 9 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 5
FWCI: 1.50
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Frontiers in Microbiology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health
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 glabrata, echinocandin resistance, cell wall integrity, beta-1,3-glucan synthase, FKS1, Slt2, caspofungin, intestinal colonization, fungal-host interactions, antifungal resistance

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Critical Assessment of Cell Wall Integrity Factors Contributing to in vivo Echinocandin Tolerance and Resistance in Candida glabrata

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