Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species
Summary Fungal infections have emerged as a major global threat to human health because of the increasing incidence and mortality rates every year. The emergence of drug resistance and limited arsenal of antifungal agents further aggravates the current situation resulting in a growing challenge in m...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-02-01
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| Series: | Microbial Biotechnology |
| Online Access: | https://doi.org/10.1111/1751-7915.13814 |
| _version_ | 1819283663095857152 |
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| author | Lin Liu Tong Jiang Jia Zhou Yikun Mei Jinyang Li Jingcong Tan Luqi Wei Jingquan Li Yibing Peng Changbin Chen Ning‐Ning Liu Hui Wang |
| author_facet | Lin Liu Tong Jiang Jia Zhou Yikun Mei Jinyang Li Jingcong Tan Luqi Wei Jingquan Li Yibing Peng Changbin Chen Ning‐Ning Liu Hui Wang |
| author_sort | Lin Liu |
| collection | DOAJ |
| description | Summary Fungal infections have emerged as a major global threat to human health because of the increasing incidence and mortality rates every year. The emergence of drug resistance and limited arsenal of antifungal agents further aggravates the current situation resulting in a growing challenge in medical mycology. Here, we identified that ponatinib, an FDA‐approved antitumour drug, significantly enhanced the activity of the azole fluconazole, the most widely used antifungal drug. Further detailed investigation of ponatinib revealed that its combination with fluconazole displayed broad‐spectrum synergistic interactions against a variety of human fungal pathogens such as Candida albicans, Saccharomyces cerevisiae and Cryptococcus neoformans. Mechanistic insights into the mode of action unravelled that ponatinib reduced the efflux of fluconazole via Pdr5 and suppressed the expression of the proton pump, Pma1. Taken together, our study identifies ponatinib as a novel antifungal that enhances drug activity of fluconazole against diverse fungal pathogens. |
| first_indexed | 2024-12-24T01:35:03Z |
| format | Article |
| id | doaj.art-33e710d289164d479efa277526b7706f |
| institution | Directory Open Access Journal |
| issn | 1751-7915 |
| language | English |
| last_indexed | 2024-12-24T01:35:03Z |
| publishDate | 2022-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Microbial Biotechnology |
| spelling | doaj.art-33e710d289164d479efa277526b7706f2022-12-21T17:22:12ZengWileyMicrobial Biotechnology1751-79152022-02-0115248249810.1111/1751-7915.13814Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast speciesLin Liu0Tong Jiang1Jia Zhou2Yikun Mei3Jinyang Li4Jingcong Tan5Luqi Wei6Jingquan Li7Yibing Peng8Changbin Chen9Ning‐Ning Liu10Hui Wang11State Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaCenter for Microbes Development and Health Key Laboratory of Molecular Virology and Immunology Institut Pasteur of Shanghai Chinese Academy of Sciences Shanghai 200031 ChinaState Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaState Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaState Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaState Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaState Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaState Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaDepartment of Laboratory Medicine Ruijin Hospital Shanghai Jiao Tong University School of Medicine No. 197 Ruijin ER Road Shanghai 200025 ChinaCenter for Microbes Development and Health Key Laboratory of Molecular Virology and Immunology Institut Pasteur of Shanghai Chinese Academy of Sciences Shanghai 200031 ChinaState Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaState Key Laboratory of Oncogenes and Related Genes Center for Single‐Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaSummary Fungal infections have emerged as a major global threat to human health because of the increasing incidence and mortality rates every year. The emergence of drug resistance and limited arsenal of antifungal agents further aggravates the current situation resulting in a growing challenge in medical mycology. Here, we identified that ponatinib, an FDA‐approved antitumour drug, significantly enhanced the activity of the azole fluconazole, the most widely used antifungal drug. Further detailed investigation of ponatinib revealed that its combination with fluconazole displayed broad‐spectrum synergistic interactions against a variety of human fungal pathogens such as Candida albicans, Saccharomyces cerevisiae and Cryptococcus neoformans. Mechanistic insights into the mode of action unravelled that ponatinib reduced the efflux of fluconazole via Pdr5 and suppressed the expression of the proton pump, Pma1. Taken together, our study identifies ponatinib as a novel antifungal that enhances drug activity of fluconazole against diverse fungal pathogens.https://doi.org/10.1111/1751-7915.13814 |
| spellingShingle | Lin Liu Tong Jiang Jia Zhou Yikun Mei Jinyang Li Jingcong Tan Luqi Wei Jingquan Li Yibing Peng Changbin Chen Ning‐Ning Liu Hui Wang Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species Microbial Biotechnology |
| title | Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species |
| title_full | Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species |
| title_fullStr | Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species |
| title_full_unstemmed | Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species |
| title_short | Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species |
| title_sort | repurposing the fda approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and pma1 expression in a broad spectrum of yeast species |
| url | https://doi.org/10.1111/1751-7915.13814 |
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