Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae.
Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and h...
Published in: | PLOS Neglected Tropical Diseases |
---|---|
Main Authors: | , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Public Library of Science (PLoS)
2020
|
Subjects: | |
Online Access: | https://doi.org/10.1371/journal.pntd.0008353 https://doaj.org/article/cc1de70502d44438b391b66a2a7f3dfd |
id |
ftdoajarticles:oai:doaj.org/article:cc1de70502d44438b391b66a2a7f3dfd |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:cc1de70502d44438b391b66a2a7f3dfd 2023-05-15T15:11:19+02:00 Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. Christopher A Rice Beatrice L Colon Emily Chen Mitchell V Hull Dennis E Kyle 2020-09-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0008353 https://doaj.org/article/cc1de70502d44438b391b66a2a7f3dfd EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0008353 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008353 https://doaj.org/article/cc1de70502d44438b391b66a2a7f3dfd PLoS Neglected Tropical Diseases, Vol 14, Iss 9, p e0008353 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0008353 2022-12-31T10:07:30Z Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. Since repurposing drugs is an ideal strategy for orphan diseases, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 <1 μM) against N. fowleri (n = 19), A. castellanii (n = 12), and B. mandrillaris (n = 27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 9 e0008353 |
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 Christopher A Rice Beatrice L Colon Emily Chen Mitchell V Hull Dennis E Kyle Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. Since repurposing drugs is an ideal strategy for orphan diseases, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 <1 μM) against N. fowleri (n = 19), A. castellanii (n = 12), and B. mandrillaris (n = 27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design. |
format |
Article in Journal/Newspaper |
author |
Christopher A Rice Beatrice L Colon Emily Chen Mitchell V Hull Dennis E Kyle |
author_facet |
Christopher A Rice Beatrice L Colon Emily Chen Mitchell V Hull Dennis E Kyle |
author_sort |
Christopher A Rice |
title |
Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. |
title_short |
Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. |
title_full |
Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. |
title_fullStr |
Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. |
title_full_unstemmed |
Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. |
title_sort |
discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0008353 https://doaj.org/article/cc1de70502d44438b391b66a2a7f3dfd |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 9, p e0008353 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0008353 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008353 https://doaj.org/article/cc1de70502d44438b391b66a2a7f3dfd |
op_doi |
https://doi.org/10.1371/journal.pntd.0008353 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
9 |
container_start_page |
e0008353 |
_version_ |
1766342190366195712 |