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Mechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrata

ABSTRACT: Multidrug resistance in the pathogenic fungus Candida glabrata is a growing global threat. Here, we study mechanisms of multidrug resistance in this pathogen. Exposure of C. glabrata cells to micafungin (an echinocandin) leads to the isolation of a mutant exhibiting resistance to echinocandin and azole antifungals. The drug-resistant phenotype is due to a non-synonymous mutation (R70H) in gene IPI1, which is known to be involved in pre-rRNA processing in Saccharomyces cerevisiae. Azole resistance in the ipi1-R70H mutant depends on the Pdr1 transcription factor, which regulates the expression of multidrug transporters. We show that the C. glabrata Ipi1 protein physically interacts with the ribosome-related chaperones Ssb and Ssz1, both of which bind to Pdr1. The Ipi1-Ssb/Ssz1 complex inhibits Pdr1-mediated gene expression and multidrug resistance in C. glabrata, in contrast to S. cerevisiae where Ssz1 has been shown to act as a positive regulator of Pdr1. Furthermore, micafungin exposure reduces metabolic activity and cell proliferation in the ipi1-R70H mutant, which may contribute to micafungin tolerance.

ORGANISM(S): Nakaseomyces glabratus

PROVIDER: GSE255839 | GEO | 2024/12/19

REPOSITORIES: GEO

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