Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance

Katiyar, Santosh K.; Alastruey-Izquierdo, Ana; Healey, Kelley R.; Johnson, Michael E.; Perlin, David S.; Edlind, Thomas D.

doi:10.1128/aac.00813-12

Cited by 148Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance

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Katiyar, Santosh K., Alastruey-Izquierdo, Ana, Healey, Kelley R., Johnson, Michael E., Perlin, David S., Edlind, Thomas D.·2012·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.00813-12PMC PMC3497156

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Abstract

The echinocandins caspofungin, micafungin, and anidulafungin, inhibitors of cell wall β-1,3-glucan synthesis, were recently elevated to first-line agents for treating infections due to the azole-refractory yeast Candida glabrata . In Candida albicans , echinocandin resistance is strictly associated with mutations in Fks1, a large integral membrane protein and putative β-1,3-glucan synthase, while mutations in both Fks1 and its paralog Fks2 (but not Fks3) have been associated with resistance in C. glabrata . To further explore their function, regulation, and role in resistance, C. glabrata fks genes were disrupted and subjected to mutational analysis, and their differential regulation was explored. An fks1 Δ fks2 Δ double disruptant was not able to be generated; otherwise, all three single and remaining two double disruptants displayed normal growth and echinocandin susceptibility, indicating Fks1-Fks2 redundancy. Selection on echinocandin-containing medium for resistant mutants was dependent on strain background: only fks1 Δ and fks1 Δ fks3 Δ strains consistently yielded mutants exhibiting high-level resistance, all with Fks2 hot spot 1 mutations. Thus, Fks1-Fks2 redundancy attenuates the rate of resistance; further analysis showed that it also attenuates the impact of resistance-conferring mutations. Growth of the fks1 Δ and, especially, fks1 Δ fks3 Δ strains was specifically susceptible to the calcineurin inhibitor FK506. Relatedly, FK506 addition or calcineurin gene CMP2 disruption specifically reversed Fks2-mediated resistance of laboratory mutants and clinical isolates. RNA analysis suggests that transcriptional control is not the sole mechanism by which calcineurin modulates Fks2 activity.

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Strong resistance to echinocandins arises primarily through mutations in FKS1 and FKS2, the latter of which depends on calcineurin and the Crz1 transcription factor for maximal expression.
“However, strong resistance to echinocandins arises primarily through mutations in the two targets, encoded by FKS1 and FKS2 (23, 24), the latter of which depends on calcineurin and the Crz1 transcription factor for maximal expression (25).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [25]
The Fks2-mediated resistance section (page not available in our copy) reports that calcineurin inhibition or CMP2 disruption blocks a modest induction of FKS2 expression. The Discussion says calcineurin also may regulate Fks2 activity by mechanisms other than transcription. Our copy does not identify Crz1 as a regulator or establish that calcineurin and Crz1 are required for maximal FKS2 expression. (LLM, conf=0.88)
Experimental — accuracy not yet measured
fks1∆ mutants are FK506-sensitive because they depend on calcineurin signaling, Crz1, and elevated expression of FKS2 for viability.
“The fks1∆ mutants are FK506-sensitive because they depend on calcineurin signaling, Crz1, and elevated expression of FKS2 for viability (25).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [25]
The FK506-susceptibility results (FIG 2; page unavailable) show that C. glabrata fks1Δ mutants are strongly inhibited by FK506, supporting a role for calcineurin. But the Discussion (page unavailable) says the observed effects on FKS2 expression were modest and that mechanisms other than transcriptional regulation may explain FK506 sensitivity. Our copy does not establish dependence on Crz1 or on elevated FKS2 expression for viability. (LLM, conf=0.87)
Experimental — accuracy not yet measured
FKS1 (Z = 3.38) encodes the major catalytic subunit of glucan synthase.
“One such gene is FKS1 (Z = 3.38), which encodes the major catalytic subunit of glucan synthase (25, 39, 40).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [25]
The paper’s introductory passage identifies FKS1 as encoding a putative β-1,3-glucan synthase, supporting its connection to the enzyme. It does not call Fks1 the major catalytic subunit; the Discussion instead says Fks1 and Fks2 are fully redundant for growth in Candida glabrata. The Z score appears to be the citing paper’s own result, not a finding attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Previous studies have shown that calcineurin and Crz1 also produce mild resistance to echinocandins in C. glabrata by increasing expression of the drug target, Fks2.
“Previous studies have shown that calcineurin and Crz1 also produce mild resistance to echinocandins in C. glabrata by increasing expression of the drug target, Fks2 (25) (see Fig. 9).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [25]
In “Fks2-mediated resistance is reversed by FK506” (page unavailable), the paper reports that inhibiting calcineurin or disrupting CMP2 reverses resistance associated with Fks2 mutations in C. glabrata. It also finds modest, calcineurin-dependent increases in FKS2 expression, but the Discussion says transcriptional regulation may not explain the resistance effect. Our copy does not identify a role for Crz1 or establish that calcineurin and Crz1 produce mild resistance by increasing Fks2 expression. (LLM, conf=0.89)
Experimental — accuracy not yet measured
When a resistance mutation arises in FKS2, its impact in vitro can be blocked by calcineurin inhibitors.
“When a resistance mutation arises in FKS2, its impact in vitro can be blocked by calcineurin inhibitors (25, 26).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [25]

When strong resistance mutations in FKS2 arise in patients, calcineurin inhibitors greatly diminish their impact in vitro.
“When strong resistance mutations in FKS2 arise in patients, calcineurin inhibitors greatly diminish their impact in vitro (25, 39).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [25]
The divergent FKS1/FKS2 expression in gcn5Δ suggests a potential compensatory mechanism given functional redundancy between FKS1 and FKS2.
“This finding suggests a potential compensatory mechanism, given the functional redundancy between FKS1 and FKS242–44.”
From Targeting epigenetic regulators to overcome drug resistance in the emerging human fungal pathogen Candida auris (2025) · cites this paper as [42]
FKS1 and FKS2 mutations can confer resistance to echinocandin drugs in C. glabrata.
“it is known that FKS1 and FKS2 mutations can confer resistance to echinocandin drugs in C. glabrata (Katiyar et al., 2012; Arendrup and Perlin, 2014).”
From Genome Comparisons of Candida glabrata Serial Clinical Isolates Reveal Patterns of Genetic Variation in Infecting Clonal Populations (2019) · cites this paper as Katiyar et al., 2012
In C. albicans, FKS1 is an essential gene encoding a catalytic subunit of the 1,3-β-glucan synthase complex, whereas in C. glabrata, FKS1 and FKS2 are functionally redundant for viability.
“In C. albicans, FKS1 is an essential gene encoding a catalytic subunit of the 1,3-β-glucan synthase complex, whereas in C. glabrata, FKS1 and FKS2 are functionally redundant for viability35.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [35]
The addition of caspofungin strongly induced FKS2 expression.
“The addition of caspofungin strongly induced FKS2 expression as expected [35] with this induction unaffected by the absence of Upc2A.”
From The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways (2021) · cites this paper as [35]
In C. glabrata, expression of the FKS2 gene is calcineurin-dependent, and the resistance phenotype can be reversed upon application of calcineurin inhibitors such as FK506.
“Additionally, in C. glabrata, the expression of the FKS2 gene has been shown to be calcineurin-dependent, and the resistance phenotype can be reversed upon the application of calcineurin inhibitors such as FK506 [109].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [109]

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Authors: Katiyar, S. K., Alastruey-Izquierdo, A., Healey, K. R., Johnson, M. E., Perlin, D. S., & Edlind, T. D.
Affiliations: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
Drexel University (US)
Rutgers New Jersey Medical School (US)
ORCID: Healey, Kelley R.
Perlin, David S.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2012-12
Volume: 56
Issue: 12
Pages: 6304-6309
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.00813-12
PMC: PMC3497156
OpenAlex: W1997382339
Cited by: 148
References: 46
Citations by year: 2026: 15 · 2025: 17 · 2024: 10 · 2023: 9 · 2022: 9 · 2021: 14 · 2020: 12 · 2019: 16 · 2018: 9 · 2017: 6 · 2016: 8 · 2015: 7 · 2014: 11 · 2013: 5
FWCI: 5.08
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Pfizer
National Institutes of Health
National Institute of Allergy and Infectious Diseases (AI069397, AI075272., R01AI069397, R01AI075272)
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, FKS1, FKS2, beta-1,3-glucan synthase, functional redundancy, caspofungin, micafungin, anidulafungin, calcineurin, FK506, transcriptional regulation, antifungal resistance, clinical isolates
MeSH terms: Antifungal Agents, Culture Media, Fungal Proteins, Genes, Fungal, Glucosyltransferases, Immunosuppressive Agents, Membrane Proteins, Molecular Sequence Data, Mutation, Plasmids, RNA, Polymerase Chain Reaction, Tacrolimus, Calcineurin, Drug Resistance, Fungal, Candida glabrata, Echinocandins

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Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance

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