Cut the Kinase, Break the Resistance

Review written by: Megan Mauriello

Candida glabrata, now officially known as Nakaseomyces glabratus (Takashima and Sugita 2022), causes opportunistic infections, especially in immunocompromised people, and has a high mortality rate. It is among the most frequently antifungal-resistant Candida species. Echinocandin antifungals, including caspofungin, micafungin, anidulafungin, and rezafungin, inhibit fungal cell wall synthesis by inhibiting β-1,3-glucan synthase. Echinocandin resistance is usually related to mutations in FKS1 or FKS2, with each encoding the catalytic subunit of β-1,3-glucan synthase. In C. glabrata, FKS1 and FKS2 are functionally redundant, but their mechanisms of transcriptional regulation differ. Clinical resistance is primarily associated with mutations in either FKS1 or FKS2. Triazole antifungals, including fluconazole, voriconazole, and itraconazole, target lanosterol 14α-demethylase, which is involved in ergosterol synthesis. Triazole resistance is typically associated with substitutions in the Pdr1 transcription factor, which leads to overexpression of ATP-binding cassette (ABC) efflux pump. The cell wall integrity pathway has previously been shown to be involved in antifungal tolerance. It is activated by plasma-membrane spanning sensors including Slg1, which cluster when the cell wall is disturbed. Activation leads to activation of Protein Kinase C (Pkc1) and a MAP kinase (MAPK) cascade, with Slt2 being the terminal MAPK. Slt2 activates transcription factors, leading to transcriptional activation of a suite of cell wall related genes.

Figure. Strains deleted for SLT2 exhibited consistent decreases in FKS2 expression following echinocandin exposure.

Disruption of SLT2 abolished C. glabrata micafungin or caspofungin (echinocandin) resistance when FKS2, but not FKS1, was mutated, and complementation of these strains with plasma-borne SLT2 restored resistance, wholly or partially, in FKS2 mutants. FKS2 expression decreased significantly in strains with disrupted SLT2 compared to those with intact SLT2 after exposure to caspofungin. FKS1 expression increased modestly in wild-type and FKS2 mutant strains with disrupted SLT2 after exposure to caspofungin, which the authors speculate is compensatory in response to reduced FKS2 expression. Disruption of SLT2 in pdr1 mutants did not affect fluconazole or voriconazole (triazole) resistance.

C. glabrata has high rates of acquired antifungal resistance, with 3-12% of strains exhibiting echinocandin resistance and 8-13% of strains exhibiting fluconazole (triazole) resistance. This study enhances scientific understanding of important drug target genes, and even hints at a potential new therapeutic target for echinodandin-resistant infections: the cell wall integrity pathway and Slt2.

In a previous study, a C. glabrata gastrointestinal infection in mice was cleared more effectively when the cells lacked SLT2, and echinocandin-resistant strains were less likely to evolve. In that study, a FKS2 mutant (with deleted SLT2) isolated from mice was susceptible to echinocandins in vitro, an observation which can be explained by Slt2-mediation of FKS2.

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READ MORE:

Uddin Z, Tahsin S, Valickova K, Long T, Fruhauf De Macedo L, Popencuk G, Zhao Y, Healey KR.2026.Slt2 kinase of the cell wall integrity pathway is required for Fks2-specific echinocandin resistance in Candida glabrata. Microbiol Spectr14:e03874-25. https://doi.org/10.1128/spectrum.03874-25

Takashima M, Sugita T. Taxonomy of Pathogenic Yeasts Candida, Cryptococcus, Malassezia, and Trichosporon. Med Mycol J. 2022;63(4):119-132. doi: 10.3314/mmj.22.004. PMID: 36450564.