Genotypic, proteomic, and phenotypic approaches to decipher the response to caspofungin and calcineurin inhibitors in clinical isolates of echinocandin-resistant Candida glabrata

Ceballos-Garzon, Andres; Monteoliva, Lucia; Gil, Concha; Alvarez-Moreno, Carlos; Vega-Vela, Nelson E; Engelthaler, David M; Bowers, Jolene; Le Pape, Patrice; Parra-Giraldo, Claudia M

doi:10.1093/jac/dkab454

Cited by 18Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Genotypic, proteomic, and phenotypic approaches to decipher the response to caspofungin and calcineurin inhibitors in clinical isolates of echinocandin-resistant Candida glabrata

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Ceballos-Garzon, Andres, Monteoliva, Lucia, Gil, Concha, Alvarez-Moreno, Carlos, Vega-Vela, Nelson E, Engelthaler, David M, Bowers, Jolene, Le Pape, Patrice +1 more·2022·Journal of Antimicrobial Chemotherapy

DOI 10.1093/jac/dkab454PMC PMC8865013

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Abstract

Background: Echinocandin resistance represents a great concern, as these drugs are recommended as first-line therapy for invasive candidiasis. Echinocandin resistance is conferred by mutations in FKS genes. Nevertheless, pathways are crucial for enabling tolerance, evolution, and maintenance of resistance. Therefore, understanding the biological processes and proteins involved in the response to caspofungin may provide clues indicating new therapeutic targets. Objectives: We determined the resistance mechanism and assessed the proteome response to caspofungin exposure. We then evaluated the phenotypic impact of calcineurin inhibition by FK506 and cephalosporine A (CsA) on caspofungin-resistant Candida glabrata isolates. Methods: Twenty-five genes associated with caspofungin resistance were analysed by NGS, followed by studies of the quantitative proteomic response to caspofungin exposure. Then, susceptibility testing of caspofungin in presence of FK506 and CsA was performed. The effects of calcineurin inhibitor/caspofungin combinations on heat stress (40°C), oxidative stress (0.2 and 0.4 mM menadione) and on biofilm formation (polyurethane catheter) were analysed. Finally, a Galleria mellonella model using blastospores (1 × 109 cfu/mL) was developed to evaluate the impact of the combinations on larval survival. Results: F659-del was found in the FKS2 gene of resistant strains. Proteomics data showed some up-regulated proteins are involved in cell-wall biosynthesis, response to stress and pathogenesis, some of them being members of calmodulin–calcineurin pathway. Therefore, the impact of calmodulin inhibition was explored. Calmodulin inhibition restored caspofungin susceptibility, decreased capacity to respond to stress conditions, and reduced biofilm formation and in vivo pathogenicity. Conclusions: Our findings confirm that calmodulin-calcineurin-Crz1 could provide a relevant target in life-threatening invasive candidiasis.

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The FKS2 F659del mutation has been reported to contribute to elevated echinocandin MICs.
“This specific mutation has also been reported for its contribution to elevated echinocandin MICs [38, 41].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in Candida Glabrata (2026) · cites this paper as [41]

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Functional characterization of the regulators of calcineurin in Candida glabrata
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Calcineurin-dependent contributions to fitness in the opportunistic pathogen Candida glabrata
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“This specific mutation has also been reported for its contribution to elevated echinocandin MICs [ 38, 41 ].”

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Authors: Ceballos-Garzon, A., Monteoliva, L., Gil, C., Alvarez-Moreno, C., Vega-Vela, N. E., Engelthaler, D. M., Bowers, J., Le Pape, P., & Parra-Giraldo, C. M.
Affiliations: Unidad de Proteómica y Micosis Humanas, Grupo de Enfermedades Infecciosas Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, D.C., Colombia
Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
Universidad Complutense de Madrid (ES)
Department of Internal Medicine, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
Pontificia Universidad Javeriana (CO)
Translational Genomics Research Institute (US)
Department of Parasitology and Medical Mycology, Faculty of Pharmacy, University of Nantes, Nantes Atlantique Universities, Nantes, France
ORCID: Ceballos-Garzon, Andres
Gil, Concha
Vega-Vela, Nelson E
Engelthaler, David M
Bowers, Jolene
Le Pape, Patrice
Parra-Giraldo, Claudia M
Venue: Journal of Antimicrobial Chemotherapy
Publisher: Oxford University Press (OUP)
Published: 2021-12-10
Volume: 77
Issue: 3
Pages: 585-597
ISSN: 0305-7453 (ISSN-L)
1460-2091
DOI: 10.1093/jac/dkab454
PMC: PMC8865013
OpenAlex: W4200334417
Cited by: 18
References: 84
Citations by year: 2026: 3 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 6 · 2021: 1
FWCI: 0.95
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0/ (vor)
Locations: Journal of Antimicrobial Chemotherapy (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
HAL (submittedVersion, cc-by)
Funders: Ministerio de Ciencia, Tecnología e Innovación
Universidad Complutense de Madrid
Campus France
Pontificia Universidad Javeriana (ID20291)
Instituto de Salud Carlos III
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: Candida glabrata, echinocandin resistance, caspofungin, calcineurin inhibitors, FK506, biofilm formation, oxidative stress response, heat stress, invasive candidiasis, Galleria mellonella model, antifungal drug targets
MeSH terms: Caspofungin, Antifungal Agents, Fungal Proteins, Microbial Sensitivity Tests, Drug Resistance, Fungal, Proteomics, Candida glabrata, Echinocandins, Candidiasis, Invasive, Calcineurin Inhibitors

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Genotypic, proteomic, and phenotypic approaches to decipher the response to caspofungin and calcineurin inhibitors in clinical isolates of echinocandin-resistant Candida glabrata

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