Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling
Open accessAbstract
Expanding echinocandin use to prevent or treat invasive fungal infections has led to an increase in the number of breakthrough infections due to resistant Candida species. Although it is uncommon, echinocandin resistance is well documented for Candida albicans , which is among the most prevalent bloodstream organisms. A better understanding is needed to assess the cellular factors that promote tolerance and predispose infecting cells to clinical breakthrough. We previously showed that some mutants that were adapted to growth in the presence of toxic sorbose due to loss of one chromosome 5 (Ch5) also became more tolerant to caspofungin. We found here, following direct selection of mutants on caspofungin, that tolerance can be conferred by at least three mechanisms: (i) monosomy of Ch5, (ii) combined monosomy of the left arm and trisomy of the right arm of Ch5, and (iii) an aneuploidy-independent mechanism. Tolerant mutants possessed cell walls with elevated chitin and showed downregulation of genes involved in cell wall biosynthesis, namely, FKS , located outside Ch5, and CHT2 , located on Ch5, irrespective of Ch5 ploidy. Also irrespective of Ch5 ploidy, the CNB1 and MID1 genes on Ch5, which are involved in the calcineurin signaling pathway, were expressed at the diploid level. Thus, multiple mechanisms can affect the relative expression of the aforementioned genes, controlling them in similar ways. Although breakthrough mutations in two specific regions of FKS1 have previously been associated with caspofungin resistance, we found mechanisms of caspofungin tolerance that are independent of FKS1 and thus represent an earlier event in resistance development.
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Genome changes such as whole-chromosome aneuploidy and shorter amplifications can raise resistance.
“Copy number variations, including whole-chromosome aneuploidy and shorter-range amplifications, are genome changes that can increase resistance32,43–49.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [46]
Cell wall remodeling contributes to echinocandin tolerance, with changes in β-glucan synthesis or increased production of compensatory components like chitin strengthening the cell wall and reducing drug efficacy.
“Cell wall remodeling contributes to echinocandin tolerance, with changes in β-glucan synthesis or increased production of compensatory components, like chitin, strengthening the cell wall and reducing drug efficacy [118,119].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [118]
Drug exposure, such as with prophylactic or recurrent ECN treatment, further enhances the selection of resistance.
“Drug exposure, such as with prophylactic or recurrent ECN treatment, further enhances the selection of resistance (39, 75).”
From Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris (2022) · cites this paper as [39]
In C. albicans, some echinocandin-tolerant mutants showed either monosomy of chromosome 5 or combined monosomy of the left arm and trisomy of the right arm of chromosome 5.
“In C. albicans, other relevant components for echinocandin tolerance may be located at chromosome 5 (Ch5), since some tolerant mutants showed either monosomy of the Ch5, or combined monosomy of the left arm and trisomy of the right arm of Ch5 (Yang et al., 2017).”
From Fungal Cell Wall: Emerging Antifungals and Drug Resistance. (2019) · cites this paper as Yang et al., 2017
Positive regulators of echinocandin susceptibility include CNB1 and MID1.
“They also found positive regulators, i.e., CNB1 encoding a regulatory subunit of calcineurin B, and MID1 encoding a putative stretch-activated Ca2+ channel of the high-affinity calcium uptake system [118].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [118]
Besides mutations in FKS1, additional regulators have been linked to increased CSP tolerance in other Candida spp., including Candida glabrata.
“Besides mutations in FKS1, additional regulators have been linked to increased CSP tolerance in other Candida spp., including Candida glabrata (39, 43, 74).”
From Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris (2022) · cites this paper as [39]
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Self-citation
- Authors
- Yang, F., Zhang, L., Wakabayashi, H., Myers, J., Jiang, Y., Cao, Y., Jimenez-Ortigosa, C., Perlin, D. S., & Rustchenko, E.
- Affiliations
- University of Rochester Medicine (US)
- Second Military Medical University (CN)
- Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA
- Rutgers Health (US)
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2017-05
- Volume
- 61
- Issue
- 5
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC5404545
- OpenAlex
- W2590904034
- Cited by
- 81
- References
- 41
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 7 · 2023: 11 · 2022: 11 · 2021: 13 · 2020: 11 · 2019: 10 · 2018: 5 · 2017: 1
- FWCI
- 5.68
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-03-27)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (AI110764, AI109025)
- National Natural Science Foundation of China (81173100, 81273556)
- Merck (MISP award 51184)
- University of Rochester
- 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
- echinocandin resistance, Candida albicans, cell wall remodeling, monosomy, trisomy, chitin, calcineurin signaling, MID1, breakthrough infection, antifungal resistance
- MeSH terms
- Caspofungin, Antifungal Agents, Candida albicans, Cell Wall, Chitin, Chitinases, Humans, Membrane Glycoproteins, Microbial Sensitivity Tests, Calcineurin, Drug Resistance, Fungal, beta-Glucans, Echinocandins, Lipopeptides
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