Cisplatin protects mice from challenge of Cryptococcus neoformans by targeting the Prp8 intein
ABSTRACTThe Prp8 intein is one of the most widespread eukaryotic inteins, present in important pathogenic fungi, including Cryptococcus and Aspergillus species. Because the processed Prp8 carries out essential and non-redundant cellular functions, a Prp8 intein inhibitor is a mechanistically novel a...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Emerging Microbes and Infections |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2019.1625727 |
| _version_ | 1797385770646896640 |
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| author | Zhong Li Bin Fu Cathleen M. Green Binbin Liu Jing Zhang Yuekun Lang Sudha Chaturvedi Marlene Belfort Guojian Liao Hongmin Li |
| author_facet | Zhong Li Bin Fu Cathleen M. Green Binbin Liu Jing Zhang Yuekun Lang Sudha Chaturvedi Marlene Belfort Guojian Liao Hongmin Li |
| author_sort | Zhong Li |
| collection | DOAJ |
| description | ABSTRACTThe Prp8 intein is one of the most widespread eukaryotic inteins, present in important pathogenic fungi, including Cryptococcus and Aspergillus species. Because the processed Prp8 carries out essential and non-redundant cellular functions, a Prp8 intein inhibitor is a mechanistically novel antifungal agent. In this report, we demonstrated that cisplatin, an FDA-approved cancer drug, significantly arrested growth of Prp8 intein-containing fungi C. neoformans and C. gattii, but only poorly inhibited growth of intein-free Candida species. These results suggest that cisplatin arrests fungal growth through specific inhibition of the Prp8 intein. Cisplatin was also found to significantly inhibit growth of C. neoformans in a mouse model. Our results further showed that cisplatin inhibited Prp8 intein splicing in vitro in a dose-dependent manner by direct binding to the Prp8 intein. Crystal structures of the apo- and cisplatin-bound Prp8 inteins revealed that two degenerate cisplatin molecules bind at the intein active site. Mutation of the splicing-site residues led to loss of cisplatin binding, as well as impairment of intein splicing. Finally, we found that overexpression of the Prp8 intein in cryptococcal species conferred cisplatin resistance. Overall, these results indicate that the Prp8 intein is a novel antifungal target worth further investigation. |
| first_indexed | 2024-03-08T21:59:04Z |
| format | Article |
| id | doaj.art-8083ea2850c44e5392a0f6ca9df816df |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-03-08T21:59:04Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-8083ea2850c44e5392a0f6ca9df816df2023-12-19T16:09:57ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512019-01-018189590810.1080/22221751.2019.1625727Cisplatin protects mice from challenge of Cryptococcus neoformans by targeting the Prp8 inteinZhong Li0Bin Fu1Cathleen M. Green2Binbin Liu3Jing Zhang4Yuekun Lang5Sudha Chaturvedi6Marlene Belfort7Guojian Liao8Hongmin Li9New York State Department of Health, Wadsworth Center, Albany, NY, USACollege of Pharmaceutical Sciences, Southwest University, Chongqing, People’s Republic of ChinaDepartment of Biological Sciences and RNA Institute, University at Albany, Albany, NY, USANew York State Department of Health, Wadsworth Center, Albany, NY, USANew York State Department of Health, Wadsworth Center, Albany, NY, USANew York State Department of Health, Wadsworth Center, Albany, NY, USANew York State Department of Health, Wadsworth Center, Albany, NY, USADepartment of Biological Sciences and RNA Institute, University at Albany, Albany, NY, USACollege of Pharmaceutical Sciences, Southwest University, Chongqing, People’s Republic of ChinaNew York State Department of Health, Wadsworth Center, Albany, NY, USAABSTRACTThe Prp8 intein is one of the most widespread eukaryotic inteins, present in important pathogenic fungi, including Cryptococcus and Aspergillus species. Because the processed Prp8 carries out essential and non-redundant cellular functions, a Prp8 intein inhibitor is a mechanistically novel antifungal agent. In this report, we demonstrated that cisplatin, an FDA-approved cancer drug, significantly arrested growth of Prp8 intein-containing fungi C. neoformans and C. gattii, but only poorly inhibited growth of intein-free Candida species. These results suggest that cisplatin arrests fungal growth through specific inhibition of the Prp8 intein. Cisplatin was also found to significantly inhibit growth of C. neoformans in a mouse model. Our results further showed that cisplatin inhibited Prp8 intein splicing in vitro in a dose-dependent manner by direct binding to the Prp8 intein. Crystal structures of the apo- and cisplatin-bound Prp8 inteins revealed that two degenerate cisplatin molecules bind at the intein active site. Mutation of the splicing-site residues led to loss of cisplatin binding, as well as impairment of intein splicing. Finally, we found that overexpression of the Prp8 intein in cryptococcal species conferred cisplatin resistance. Overall, these results indicate that the Prp8 intein is a novel antifungal target worth further investigation.https://www.tandfonline.com/doi/10.1080/22221751.2019.1625727CisplatinantifungalCryptococcusPrp8 inteinmouse model |
| spellingShingle | Zhong Li Bin Fu Cathleen M. Green Binbin Liu Jing Zhang Yuekun Lang Sudha Chaturvedi Marlene Belfort Guojian Liao Hongmin Li Cisplatin protects mice from challenge of Cryptococcus neoformans by targeting the Prp8 intein Emerging Microbes and Infections Cisplatin antifungal Cryptococcus Prp8 intein mouse model |
| title | Cisplatin protects mice from challenge of Cryptococcus neoformans by targeting the Prp8 intein |
| title_full | Cisplatin protects mice from challenge of Cryptococcus neoformans by targeting the Prp8 intein |
| title_fullStr | Cisplatin protects mice from challenge of Cryptococcus neoformans by targeting the Prp8 intein |
| title_full_unstemmed | Cisplatin protects mice from challenge of Cryptococcus neoformans by targeting the Prp8 intein |
| title_short | Cisplatin protects mice from challenge of Cryptococcus neoformans by targeting the Prp8 intein |
| title_sort | cisplatin protects mice from challenge of cryptococcus neoformans by targeting the prp8 intein |
| topic | Cisplatin antifungal Cryptococcus Prp8 intein mouse model |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2019.1625727 |
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