A gene network regulating echinocandin heteroresistance in Candida glabrata
- 1Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA
Abstract
While pathogenic fungi can acquire resistance to the current arsenal of antifungals through genetic mutations, heteroresistance has emerged as an important new cause of therapeutic failures. Heteroresistance is generally thought to arise in small subpopulations that display phenotypic resistance to antifungals without genetic mutations. This study blurs that line by showing gain-of-resistance (GOR) mutations in FKS2, which encodes a target of echinocandins and fungerps, causing broad heteroresistance in Candida glabrata. Identical gain-of-resistance mutations in FKS1, a paralog of FKS2, caused resistance and little or no heteroresistance. Heteroresistance of FKS2-GOR strains decreased when stress-responsive transcription factors (Crz1 and Rlm1) known to increase FKS2 expression were eliminated and was nearly abolished when the upstream regulators (calcineurin and Slt2) were mutated or inhibited. Conversely, stresses and mutations known to increase FKS2 expression also increased the survival of FKS2-GOR mutants exposed to high doses of echinocandins. A genome-wide screen using transposon sequencing revealed additional regulators of heteroresistance and resistance. Mutants lacking DFG5 or SSK2 exhibited strongly increased FKS2-GOR function without increased expression. Mutants lacking IRA1, an inhibitor of the Ras1-PKA signaling pathway that senses glucose availability, decreased expression of FKS2 and increased expression of FKS1, thereby decreasing heteroresistance and increasing resistance, respectively, when these genes carried GOR mutations. The findings suggest that heterogeneous expression of resistance genes and heterogeneous regulation of their products combine to produce echinocandin heteroresistance. Analogous mechanisms may facilitate heteroresistance to azoles and echinocandins in other Candida species.
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BibTeX
@article{harrington2026gene,
title = {{A gene network regulating echinocandin heteroresistance in Candida glabrata}},
author = {Abigail A. Harrington and Kyle W. Cunningham},
journal = {Antimicrobial Agents and Chemotherapy},
year = {2026},
month = oct,
doi = {10.1128/aac.00549-26},
url = {https://doi.org/10.1128/aac.00549-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A gene network regulating echinocandin heteroresistance in Candida glabrata
AU - Abigail A. Harrington
AU - Kyle W. Cunningham
PY - 2026
DA - 2026/10/08
JO - Antimicrobial Agents and Chemotherapy
DO - 10.1128/aac.00549-26
UR - https://doi.org/10.1128/aac.00549-26
AB - While pathogenic fungi can acquire resistance to the current arsenal of antifungals through genetic mutations, heteroresistance has emerged as an important new cause of therapeutic failures. Heteroresistance is generally thought to arise in small subpopulations that display phenotypic resistance to antifungals without genetic mutations. This study blurs that line by showing gain-of-resistance (GOR) mutations in FKS2, which encodes a target of echinocandins and fungerps, causing broad heteroresistance in Candida glabrata. Identical gain-of-resistance mutations in FKS1, a paralog of FKS2, caused resistance and little or no heteroresistance. Heteroresistance of FKS2-GOR strains decreased when stress-responsive transcription factors (Crz1 and Rlm1) known to increase FKS2 expression were eliminated and was nearly abolished when the upstream regulators (calcineurin and Slt2) were mutated or inhibited. Conversely, stresses and mutations known to increase FKS2 expression also increased the survival of FKS2-GOR mutants exposed to high doses of echinocandins. A genome-wide screen using transposon sequencing revealed additional regulators of heteroresistance and resistance. Mutants lacking DFG5 or SSK2 exhibited strongly increased FKS2-GOR function without increased expression. Mutants lacking IRA1, an inhibitor of the Ras1-PKA signaling pathway that senses glucose availability, decreased expression of FKS2 and increased expression of FKS1, thereby decreasing heteroresistance and increasing resistance, respectively, when these genes carried GOR mutations. The findings suggest that heterogeneous expression of resistance genes and heterogeneous regulation of their products combine to produce echinocandin heteroresistance. Analogous mechanisms may facilitate heteroresistance to azoles and echinocandins in other Candida species.
SN - 1098-6596
SN - 0066-4804
ER -