Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G
Protein kinase G (PknG) is a eukaryotic-like serine/threonine kinase that is expressed by Mycobacterium tuberculosis and promotes survival of mycobacteria in host macrophages by suppressing phagosome-lysosome fusion. Thus, compounds showing inhibitory activity against PknG are promising anti-mycobac...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-07-01
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| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2018.01517/full |
| _version_ | 1818525956002807808 |
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| author | Yuichi Kanehiro Haruaki Tomioka Jean Pieters Yutaka Tatano Hyoji Kim Hisashi Iizasa Hironori Yoshiyama |
| author_facet | Yuichi Kanehiro Haruaki Tomioka Jean Pieters Yutaka Tatano Hyoji Kim Hisashi Iizasa Hironori Yoshiyama |
| author_sort | Yuichi Kanehiro |
| collection | DOAJ |
| description | Protein kinase G (PknG) is a eukaryotic-like serine/threonine kinase that is expressed by Mycobacterium tuberculosis and promotes survival of mycobacteria in host macrophages by suppressing phagosome-lysosome fusion. Thus, compounds showing inhibitory activity against PknG are promising anti-mycobacterial agents. We therefore aimed to develop anti-mycobacterial agents by identifying new PknG inhibitors. A luciferase-based PknG kinase assay was used to screen potential inhibitors of PknG. We found that four compounds, namely AZD7762, R406, R406-free base, and CYC116, inhibited PknG activities. AZD7762, R406, and R406-free base promoted transfer of mycobacteria to lysosomes. These compounds also inhibited survival of M. bovis Bacillus Calmette–Guérin (BCG) inside human macrophages. Furthermore, R406 and R406-free base showed bactericidal activity against BCG in infected human macrophages without cytotoxicity. The PknG inhibitors identified in this study by the luciferase-based PknG kinase assay may be promising leads for the development of anti-mycobacterial agents. |
| first_indexed | 2024-12-11T06:16:17Z |
| format | Article |
| id | doaj.art-2e756f4a39154bb3a012ba76f3b98cd0 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-11T06:16:17Z |
| publishDate | 2018-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-2e756f4a39154bb3a012ba76f3b98cd02022-12-22T01:17:58ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2018-07-01910.3389/fmicb.2018.01517333243Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase GYuichi Kanehiro0Haruaki Tomioka1Jean Pieters2Yutaka Tatano3Hyoji Kim4Hisashi Iizasa5Hironori Yoshiyama6Department of Microbiology, Faculty of Medicine, Shimane University, Izumo, JapanDepartment of Basic Medical Sciences for Nursing, Yasuda Women’s University, Hiroshima, JapanBiozentrum, University of Basel, Basel, SwitzerlandDepartment of Pharmaceutical Science, International University of Health and Welfare, Ohtawara, JapanDepartment of Microbiology, Faculty of Medicine, Shimane University, Izumo, JapanDepartment of Microbiology, Faculty of Medicine, Shimane University, Izumo, JapanDepartment of Microbiology, Faculty of Medicine, Shimane University, Izumo, JapanProtein kinase G (PknG) is a eukaryotic-like serine/threonine kinase that is expressed by Mycobacterium tuberculosis and promotes survival of mycobacteria in host macrophages by suppressing phagosome-lysosome fusion. Thus, compounds showing inhibitory activity against PknG are promising anti-mycobacterial agents. We therefore aimed to develop anti-mycobacterial agents by identifying new PknG inhibitors. A luciferase-based PknG kinase assay was used to screen potential inhibitors of PknG. We found that four compounds, namely AZD7762, R406, R406-free base, and CYC116, inhibited PknG activities. AZD7762, R406, and R406-free base promoted transfer of mycobacteria to lysosomes. These compounds also inhibited survival of M. bovis Bacillus Calmette–Guérin (BCG) inside human macrophages. Furthermore, R406 and R406-free base showed bactericidal activity against BCG in infected human macrophages without cytotoxicity. The PknG inhibitors identified in this study by the luciferase-based PknG kinase assay may be promising leads for the development of anti-mycobacterial agents.https://www.frontiersin.org/article/10.3389/fmicb.2018.01517/fulleukaryotic-like serine/threonine kinasePknGmacrophagesphagolysosomeanti-mycobacterialchemotherapy |
| spellingShingle | Yuichi Kanehiro Haruaki Tomioka Jean Pieters Yutaka Tatano Hyoji Kim Hisashi Iizasa Hironori Yoshiyama Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G Frontiers in Microbiology eukaryotic-like serine/threonine kinase PknG macrophages phagolysosome anti-mycobacterial chemotherapy |
| title | Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G |
| title_full | Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G |
| title_fullStr | Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G |
| title_full_unstemmed | Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G |
| title_short | Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G |
| title_sort | identification of novel mycobacterial inhibitors against mycobacterial protein kinase g |
| topic | eukaryotic-like serine/threonine kinase PknG macrophages phagolysosome anti-mycobacterial chemotherapy |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2018.01517/full |
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