Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts
Human babesiosis is a global emerging tick-borne disease caused by infection with intra-erythrocytic parasites of the genus Babesia. With the rise in human babesiosis cases, the discovery and development of new anti-Babesia drugs are essential. Phosphatidylinositol 4-kinase (PI4K) is a widely presen...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2022.1048962/full |
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| author | Shengwei Ji Eloiza May Galon Moaz M. Amer Moaz M. Amer Iqra Zafar Masashi Yanagawa Masahito Asada Jinlin Zhou Mingming Liu Xuenan Xuan |
| author_facet | Shengwei Ji Eloiza May Galon Moaz M. Amer Moaz M. Amer Iqra Zafar Masashi Yanagawa Masahito Asada Jinlin Zhou Mingming Liu Xuenan Xuan |
| author_sort | Shengwei Ji |
| collection | DOAJ |
| description | Human babesiosis is a global emerging tick-borne disease caused by infection with intra-erythrocytic parasites of the genus Babesia. With the rise in human babesiosis cases, the discovery and development of new anti-Babesia drugs are essential. Phosphatidylinositol 4-kinase (PI4K) is a widely present eukaryotic enzyme that phosphorylates lipids to regulate intracellular signaling and trafficking. Previously, we have shown that MMV390048, an inhibitor of PI4K, showed potent inhibition against Babesia species, revealing PI4K as a druggable target for babesiosis. However, twice-administered, 7-day regimens failed to clear Babesia microti parasites from the immunocompromised host. Hence, in this study, we wanted to clarify whether targeting PI4K has the potential for the radical cure of babesiosis. In a B. microti-infected SCID mouse model, a 64-day-consecutive treatment with MMV390048 resulted in the clearance of parasites. Meanwhile, an atovaquone (ATO) resistant parasite line was isolated from the group treated with ATO plus azithromycin. A nonsynonymous variant in the Y272C of the cytochrome b gene was confirmed by sequencing. Likewise, MMV390048 showed potent inhibition against ATO-resistant parasites. These results provide evidence of PI4K as a viable drug target for the radical cure of babesiosis, which will contribute to designing new compounds that can eradicate parasites. |
| first_indexed | 2024-04-12T08:58:32Z |
| format | Article |
| id | doaj.art-9f94b51005684632b21312dc3b9c29c8 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-04-12T08:58:32Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-9f94b51005684632b21312dc3b9c29c82022-12-22T03:39:19ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882022-11-011210.3389/fcimb.2022.10489621048962Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hostsShengwei Ji0Eloiza May Galon1Moaz M. Amer2Moaz M. Amer3Iqra Zafar4Masashi Yanagawa5Masahito Asada6Jinlin Zhou7Mingming Liu8Xuenan Xuan9National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanBiotechnology Department, Animal Health Research Institute, Dokki, EgyptNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanDepartment of Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanShanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, ChinaSchool of Basic Medicine, Hubei University of Arts and Science, Xiangyang, ChinaNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, JapanHuman babesiosis is a global emerging tick-borne disease caused by infection with intra-erythrocytic parasites of the genus Babesia. With the rise in human babesiosis cases, the discovery and development of new anti-Babesia drugs are essential. Phosphatidylinositol 4-kinase (PI4K) is a widely present eukaryotic enzyme that phosphorylates lipids to regulate intracellular signaling and trafficking. Previously, we have shown that MMV390048, an inhibitor of PI4K, showed potent inhibition against Babesia species, revealing PI4K as a druggable target for babesiosis. However, twice-administered, 7-day regimens failed to clear Babesia microti parasites from the immunocompromised host. Hence, in this study, we wanted to clarify whether targeting PI4K has the potential for the radical cure of babesiosis. In a B. microti-infected SCID mouse model, a 64-day-consecutive treatment with MMV390048 resulted in the clearance of parasites. Meanwhile, an atovaquone (ATO) resistant parasite line was isolated from the group treated with ATO plus azithromycin. A nonsynonymous variant in the Y272C of the cytochrome b gene was confirmed by sequencing. Likewise, MMV390048 showed potent inhibition against ATO-resistant parasites. These results provide evidence of PI4K as a viable drug target for the radical cure of babesiosis, which will contribute to designing new compounds that can eradicate parasites.https://www.frontiersin.org/articles/10.3389/fcimb.2022.1048962/fullBabesia microtibabesiosisphosphatidylinositol 4-kinasetreatmentMMV390048 |
| spellingShingle | Shengwei Ji Eloiza May Galon Moaz M. Amer Moaz M. Amer Iqra Zafar Masashi Yanagawa Masahito Asada Jinlin Zhou Mingming Liu Xuenan Xuan Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts Frontiers in Cellular and Infection Microbiology Babesia microti babesiosis phosphatidylinositol 4-kinase treatment MMV390048 |
| title | Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts |
| title_full | Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts |
| title_fullStr | Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts |
| title_full_unstemmed | Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts |
| title_short | Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts |
| title_sort | phosphatidylinositol 4 kinase is a viable target for the radical cure of babesia microti infection in immunocompromised hosts |
| topic | Babesia microti babesiosis phosphatidylinositol 4-kinase treatment MMV390048 |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2022.1048962/full |
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