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 echinocand...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56269-z |
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| author | 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 Hiroshi Mukae |
| author_facet | 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 Hiroshi Mukae |
| author_sort | Taiga Miyazaki |
| collection | DOAJ |
| description | 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 ipi1 R70H 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 ipi1 R70H mutant, which may contribute to micafungin tolerance. |
| format | Article |
| id | doaj-art-1570bbc6c5324e56b8af7c21f9855fab |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-1570bbc6c5324e56b8af7c21f9855fab2025-01-26T12:42:03ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-025-56269-zMechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrataTaiga Miyazaki0Shintaro Shimamura1Yohsuke Nagayoshi2Hironobu Nakayama3Akihiro Morita4Yutaka Tanaka5Yasuhiko Matsumoto6Tatsuo Inamine7Hiroshi Nishikawa8Nana Nakada9Makoto Sumiyoshi10Tatsuro Hirayama11Shigeru Kohno12Hiroshi Mukae13Division of Respirology, Rheumatology, Infectious Diseases, and Neurology, Department of Internal Medicine, Faculty of Medicine, University of MiyazakiDepartment of Respiratory Medicine, Nagasaki University Graduate School of Biomedical SciencesDepartment of Respiratory Medicine, Nagasaki University Graduate School of Biomedical SciencesFaculty of Pharmaceutical Sciences, Suzuka University of Medical SciencesFaculty of Pharmaceutical Sciences, Suzuka University of Medical SciencesDepartment of Infection and Host Defense, Tohoku Medical and Pharmaceutical UniversityDepartment of Microbiology, Meiji Pharmaceutical UniversityDepartment of Respiratory Medicine, Nagasaki University Graduate School of Biomedical SciencesDepartment of Respiratory Medicine, Nagasaki University Graduate School of Biomedical SciencesDepartment of Respiratory Medicine, Nagasaki University Graduate School of Biomedical SciencesDivision of Respirology, Rheumatology, Infectious Diseases, and Neurology, Department of Internal Medicine, Faculty of Medicine, University of MiyazakiDepartment of Respiratory Medicine, Nagasaki University Graduate School of Biomedical SciencesDepartment of Respiratory Medicine, Nagasaki University Graduate School of Biomedical SciencesDepartment of Respiratory Medicine, Nagasaki University Graduate School of Biomedical SciencesAbstract 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 ipi1 R70H 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 ipi1 R70H mutant, which may contribute to micafungin tolerance.https://doi.org/10.1038/s41467-025-56269-z |
| spellingShingle | 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 Hiroshi Mukae Mechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrata Nature Communications |
| title | Mechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrata |
| title_full | Mechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrata |
| title_fullStr | Mechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrata |
| title_full_unstemmed | Mechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrata |
| title_short | Mechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrata |
| title_sort | mechanisms of multidrug resistance caused by an ipi1 mutation in the fungal pathogen candida glabrata |
| url | https://doi.org/10.1038/s41467-025-56269-z |
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