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

Taiga Miyazaki (), Shintaro Shimamura (), Yohsuke Nagayoshi, Hironobu Nakayama, Akihiro Morita, Yutaka Tanaka, Yasuhiko Matsumoto, Tatsuo Inamine, Hiroshi Nishikawa, Nana Nakada, Makoto Sumiyoshi, Tatsuro Hirayama, Shigeru Kohno and Hiroshi Mukae
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Taiga Miyazaki: University of Miyazaki
Shintaro Shimamura: Nagasaki University Graduate School of Biomedical Sciences
Yohsuke Nagayoshi: Nagasaki University Graduate School of Biomedical Sciences
Hironobu Nakayama: Suzuka University of Medical Sciences
Akihiro Morita: Suzuka University of Medical Sciences
Yutaka Tanaka: Tohoku Medical and Pharmaceutical University
Yasuhiko Matsumoto: Meiji Pharmaceutical University
Tatsuo Inamine: Nagasaki University Graduate School of Biomedical Sciences
Hiroshi Nishikawa: Nagasaki University Graduate School of Biomedical Sciences
Nana Nakada: Nagasaki University Graduate School of Biomedical Sciences
Makoto Sumiyoshi: University of Miyazaki
Tatsuro Hirayama: Nagasaki University Graduate School of Biomedical Sciences
Shigeru Kohno: Nagasaki University Graduate School of Biomedical Sciences
Hiroshi Mukae: Nagasaki University Graduate School of Biomedical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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 involved in pre-rRNA processing. Azole resistance in the ipi1R70H mutant depends on the Pdr1 transcription factor, which regulates the expression of multidrug transporters. 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 Saccharomyces cerevisiae where Ssz1 acts as a positive regulator of Pdr1. Furthermore, micafungin exposure reduces metabolic activity and cell proliferation in the ipi1R70H mutant, which may contribute to micafungin tolerance.

Date: 2025
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DOI: 10.1038/s41467-025-56269-z

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