A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-Dichlorobenzamil on the digestive vacuole of plasmodium falciparum
Plasmodium falciparum is the etiological agent of malignant malaria and has been shown to exhibit features resembling programmed cell death. This is triggered upon treatment with low micromolar doses of chloroquine or other lysosomotrophic compounds and is associated with leakage of the digestive va...
| Main Authors: | , , , , , , , |
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| Format: | Journal Article |
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American Society for Microbiology
2014
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| Online Access: | http://hdl.handle.net/20.500.11937/51046 |
| _version_ | 1848758600911028224 |
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| author | Lee, Y. Goh, A. Ch'Ng, J. Nosten, F. Preiser, P. Pervaiz, Shazib Yadav, S. Tan, K. |
| author_facet | Lee, Y. Goh, A. Ch'Ng, J. Nosten, F. Preiser, P. Pervaiz, Shazib Yadav, S. Tan, K. |
| author_sort | Lee, Y. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Plasmodium falciparum is the etiological agent of malignant malaria and has been shown to exhibit features resembling programmed cell death. This is triggered upon treatment with low micromolar doses of chloroquine or other lysosomotrophic compounds and is associated with leakage of the digestive vacuole contents. In order to exploit this cell death pathway, we developed a high-content screening method to select compounds that can disrupt the parasite vacuole, as measured by the leakage of intravacuolar Ca2+. This assay uses the ImageStream 100, an imaging-capable flow cytometer, to assess the distribution of the fluorescent calcium probe Fluo-4. We obtained two hits from a small library of 25 test compounds, quinacrine and 3',4'-dichlorobenzamil. The ability of these compounds to permeabilize the digestive vacuole in laboratory strains and clinical isolates was validated by confocal microscopy. The hits could induce programmed cell death features in both chloroquine-sensitive and -resistant laboratory strains. Quinacrine was effective at inhibiting field isolates in a 48-h reinvasion assay regardless of artemisinin clearance status. We therefore present as proof of concept a phenotypic screening method with the potential to provide mechanistic insights to the activity of antimalarial drugs. © 2014, American Society for Microbiology. |
| first_indexed | 2025-11-14T09:46:34Z |
| format | Journal Article |
| id | curtin-20.500.11937-51046 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T09:46:34Z |
| publishDate | 2014 |
| publisher | American Society for Microbiology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-510462017-09-13T15:34:26Z A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-Dichlorobenzamil on the digestive vacuole of plasmodium falciparum Lee, Y. Goh, A. Ch'Ng, J. Nosten, F. Preiser, P. Pervaiz, Shazib Yadav, S. Tan, K. Plasmodium falciparum is the etiological agent of malignant malaria and has been shown to exhibit features resembling programmed cell death. This is triggered upon treatment with low micromolar doses of chloroquine or other lysosomotrophic compounds and is associated with leakage of the digestive vacuole contents. In order to exploit this cell death pathway, we developed a high-content screening method to select compounds that can disrupt the parasite vacuole, as measured by the leakage of intravacuolar Ca2+. This assay uses the ImageStream 100, an imaging-capable flow cytometer, to assess the distribution of the fluorescent calcium probe Fluo-4. We obtained two hits from a small library of 25 test compounds, quinacrine and 3',4'-dichlorobenzamil. The ability of these compounds to permeabilize the digestive vacuole in laboratory strains and clinical isolates was validated by confocal microscopy. The hits could induce programmed cell death features in both chloroquine-sensitive and -resistant laboratory strains. Quinacrine was effective at inhibiting field isolates in a 48-h reinvasion assay regardless of artemisinin clearance status. We therefore present as proof of concept a phenotypic screening method with the potential to provide mechanistic insights to the activity of antimalarial drugs. © 2014, American Society for Microbiology. 2014 Journal Article http://hdl.handle.net/20.500.11937/51046 10.1128/AAC.01441-13 American Society for Microbiology unknown |
| spellingShingle | Lee, Y. Goh, A. Ch'Ng, J. Nosten, F. Preiser, P. Pervaiz, Shazib Yadav, S. Tan, K. A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-Dichlorobenzamil on the digestive vacuole of plasmodium falciparum |
| title | A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-Dichlorobenzamil on the digestive vacuole of plasmodium falciparum |
| title_full | A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-Dichlorobenzamil on the digestive vacuole of plasmodium falciparum |
| title_fullStr | A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-Dichlorobenzamil on the digestive vacuole of plasmodium falciparum |
| title_full_unstemmed | A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-Dichlorobenzamil on the digestive vacuole of plasmodium falciparum |
| title_short | A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-Dichlorobenzamil on the digestive vacuole of plasmodium falciparum |
| title_sort | high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-dichlorobenzamil on the digestive vacuole of plasmodium falciparum |
| url | http://hdl.handle.net/20.500.11937/51046 |