Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity.
Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple p...
Published in: | PLOS Neglected Tropical Diseases |
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2020
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Online Access: | https://doi.org/10.1371/journal.pntd.0008150 https://doaj.org/article/4bb14f212d8f4c10b283b6aa6e0db146 |
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ftdoajarticles:oai:doaj.org/article:4bb14f212d8f4c10b283b6aa6e0db146 2023-06-11T04:09:50+02:00 Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. Gretchen Ehrenkaufer Pengyang Li Erin E Stebbins Monica M Kangussu-Marcolino Anjan Debnath Corin V White Matthew S Moser Joseph DeRisi Jolyn Gisselberg Ellen Yeh Steven C Wang Ana Hervella Company Ludovica Monti Conor R Caffrey Christopher D Huston Bo Wang Upinder Singh 2020-03-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0008150 https://doaj.org/article/4bb14f212d8f4c10b283b6aa6e0db146 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0008150 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008150 https://doaj.org/article/4bb14f212d8f4c10b283b6aa6e0db146 PLoS Neglected Tropical Diseases, Vol 14, Iss 3, p e0008150 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0008150 2023-05-28T00:35:45Z Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the previous human use of three of these drugs (obatoclax, anisomycin and nithiamide), support the idea that these compounds could serve as the basis for the development of broad-spectrum anti-parasitic drugs. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 3 e0008150 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Gretchen Ehrenkaufer Pengyang Li Erin E Stebbins Monica M Kangussu-Marcolino Anjan Debnath Corin V White Matthew S Moser Joseph DeRisi Jolyn Gisselberg Ellen Yeh Steven C Wang Ana Hervella Company Ludovica Monti Conor R Caffrey Christopher D Huston Bo Wang Upinder Singh Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the previous human use of three of these drugs (obatoclax, anisomycin and nithiamide), support the idea that these compounds could serve as the basis for the development of broad-spectrum anti-parasitic drugs. |
format |
Article in Journal/Newspaper |
author |
Gretchen Ehrenkaufer Pengyang Li Erin E Stebbins Monica M Kangussu-Marcolino Anjan Debnath Corin V White Matthew S Moser Joseph DeRisi Jolyn Gisselberg Ellen Yeh Steven C Wang Ana Hervella Company Ludovica Monti Conor R Caffrey Christopher D Huston Bo Wang Upinder Singh |
author_facet |
Gretchen Ehrenkaufer Pengyang Li Erin E Stebbins Monica M Kangussu-Marcolino Anjan Debnath Corin V White Matthew S Moser Joseph DeRisi Jolyn Gisselberg Ellen Yeh Steven C Wang Ana Hervella Company Ludovica Monti Conor R Caffrey Christopher D Huston Bo Wang Upinder Singh |
author_sort |
Gretchen Ehrenkaufer |
title |
Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. |
title_short |
Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. |
title_full |
Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. |
title_fullStr |
Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. |
title_full_unstemmed |
Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. |
title_sort |
identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0008150 https://doaj.org/article/4bb14f212d8f4c10b283b6aa6e0db146 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 3, p e0008150 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0008150 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008150 https://doaj.org/article/4bb14f212d8f4c10b283b6aa6e0db146 |
op_doi |
https://doi.org/10.1371/journal.pntd.0008150 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
3 |
container_start_page |
e0008150 |
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1768383850424041472 |