DOI: 10.1128/spectrum.03874-25 ISSN: 2165-0497
Slt2 kinase of the cell wall integrity pathway is required for Fks2-specific echinocandin resistance in
Candida glabrata
Zubayeda Uddin, Saira Tahsin, Klara Valickova, Tengfei Long, Laura Fruhauf De Macedo, Gabrielle Popencuk, Yanan Zhao, Kelley R. Healey ABSTRACT
Candida glabrata
is an opportunistic yeast that causes invasive infections in immunocompromised individuals. Echinocandin antifungals are first-line agents in the treatment of invasive candidiasis and act by inhibiting fungal cell wall synthesis by targeting β-1,3-glucan synthase. Echinocandin resistance is primarily associated with mutations in
FKS1
or
FKS2
, which encode for the catalytic subunit (Fks1 or Fks2) of the targeted glucan synthase. The cell wall integrity (CWI) pathway, including Slt2 kinase, is known to mediate tolerance to antifungal drugs, but its role in resistance is not completely defined. Here, we observed that disruption of
SLT2
abrogated echinocandin resistance due to
FKS2
, but not
FKS1,
mutation in
C. glabrata
. As expected, reintroduction of plasmid-borne
SLT2
restored elevated MICs of
fks2
mutants. RT-qPCR revealed that loss of
SLT2
led to decreased
FKS2
expression levels in wild-type and echinocandin-resistant strains following echinocandin exposure. In conclusion, the CWI pathway and Slt2 comprise a primary control mechanism for
FKS2
-mediated echinocandin resistance in
C. glabrata
.
IMPORTANCE
The higher rates of acquired antifungal resistance exhibited by
Candida glabrata
merit further understanding of resistance mechanisms including fungal regulation of drug target genes and enzymes. Here, we focused on a fungal tolerance pathway, the cell wall integrity pathway, and its requirement in
C. glabrata
echinocandin antifungal resistance. Interestingly, we found that targeting the pathway through disruption of a key protein, Slt2, reversed echinocandin resistance within one subset of resistant strains (
fks2
mutants) but not another (
fks1
mutants). Gene expression studies demonstrated the requirement of
SLT2
for full
FKS2
gene expression following echinocandin treatment. Overall, we discovered that Slt2 is specifically required for Fks2-mediated echinocandin resistance through partial regulation of
FKS2
expression. This study provides further insight into the regulation of drug target genes in
C. glabrata
and provides a possible therapeutic target for echinocandin-resistant infections caused by mutation of
FKS2
.