A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis.
Cryptosporidiosis has emerged as a leading cause of non-viral diarrhea in children under five years of age in the developing world, yet the current standard of care to treat Cryptosporidium infections, nitazoxanide, demonstrates limited and immune-dependent efficacy. Given the lack of treatments wit...
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ftdoajarticles:oai:doaj.org/article:5bea801b8d2341d98b24fb6b54aadb52 2023-05-15T15:16:27+02:00 A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. Melissa S Love Federico C Beasley Rajiv S Jumani Timothy M Wright Arnab K Chatterjee Christopher D Huston Peter G Schultz Case W McNamara 2017-02-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0005373 https://doaj.org/article/5bea801b8d2341d98b24fb6b54aadb52 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5310922?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005373 https://doaj.org/article/5bea801b8d2341d98b24fb6b54aadb52 PLoS Neglected Tropical Diseases, Vol 11, Iss 2, p e0005373 (2017) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2017 ftdoajarticles https://doi.org/10.1371/journal.pntd.0005373 2022-12-31T16:03:27Z Cryptosporidiosis has emerged as a leading cause of non-viral diarrhea in children under five years of age in the developing world, yet the current standard of care to treat Cryptosporidium infections, nitazoxanide, demonstrates limited and immune-dependent efficacy. Given the lack of treatments with universal efficacy, drug discovery efforts against cryptosporidiosis are necessary to find therapeutics more efficacious than the standard of care. To date, cryptosporidiosis drug discovery efforts have been limited to a few targeted mechanisms in the parasite and whole cell phenotypic screens against small, focused collections of compounds. Using a previous screen as a basis, we initiated the largest known drug discovery effort to identify novel anticryptosporidial agents. A high-content imaging assay for inhibitors of Cryptosporidium parvum proliferation within a human intestinal epithelial cell line was miniaturized and automated to enable high-throughput phenotypic screening against a large, diverse library of small molecules. A screen of 78,942 compounds identified 12 anticryptosporidial hits with sub-micromolar activity, including clofazimine, an FDA-approved drug for the treatment of leprosy, which demonstrated potent and selective in vitro activity (EC50 = 15 nM) against C. parvum. Clofazimine also displayed activity against C. hominis-the other most clinically-relevant species of Cryptosporidium. Importantly, clofazimine is known to accumulate within epithelial cells of the small intestine, the primary site of Cryptosporidium infection. In a mouse model of acute cryptosporidiosis, a once daily dosage regimen for three consecutive days or a single high dose resulted in reduction of oocyst shedding below the limit detectable by flow cytometry. Recently, a target product profile (TPP) for an anticryptosporidial compound was proposed by Huston et al. and highlights the need for a short dosing regimen (< 7 days) and formulations for children < 2 years. Clofazimine has a long history of use and has ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 11 2 e0005373 |
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English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Melissa S Love Federico C Beasley Rajiv S Jumani Timothy M Wright Arnab K Chatterjee Christopher D Huston Peter G Schultz Case W McNamara A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Cryptosporidiosis has emerged as a leading cause of non-viral diarrhea in children under five years of age in the developing world, yet the current standard of care to treat Cryptosporidium infections, nitazoxanide, demonstrates limited and immune-dependent efficacy. Given the lack of treatments with universal efficacy, drug discovery efforts against cryptosporidiosis are necessary to find therapeutics more efficacious than the standard of care. To date, cryptosporidiosis drug discovery efforts have been limited to a few targeted mechanisms in the parasite and whole cell phenotypic screens against small, focused collections of compounds. Using a previous screen as a basis, we initiated the largest known drug discovery effort to identify novel anticryptosporidial agents. A high-content imaging assay for inhibitors of Cryptosporidium parvum proliferation within a human intestinal epithelial cell line was miniaturized and automated to enable high-throughput phenotypic screening against a large, diverse library of small molecules. A screen of 78,942 compounds identified 12 anticryptosporidial hits with sub-micromolar activity, including clofazimine, an FDA-approved drug for the treatment of leprosy, which demonstrated potent and selective in vitro activity (EC50 = 15 nM) against C. parvum. Clofazimine also displayed activity against C. hominis-the other most clinically-relevant species of Cryptosporidium. Importantly, clofazimine is known to accumulate within epithelial cells of the small intestine, the primary site of Cryptosporidium infection. In a mouse model of acute cryptosporidiosis, a once daily dosage regimen for three consecutive days or a single high dose resulted in reduction of oocyst shedding below the limit detectable by flow cytometry. Recently, a target product profile (TPP) for an anticryptosporidial compound was proposed by Huston et al. and highlights the need for a short dosing regimen (< 7 days) and formulations for children < 2 years. Clofazimine has a long history of use and has ... |
format |
Article in Journal/Newspaper |
author |
Melissa S Love Federico C Beasley Rajiv S Jumani Timothy M Wright Arnab K Chatterjee Christopher D Huston Peter G Schultz Case W McNamara |
author_facet |
Melissa S Love Federico C Beasley Rajiv S Jumani Timothy M Wright Arnab K Chatterjee Christopher D Huston Peter G Schultz Case W McNamara |
author_sort |
Melissa S Love |
title |
A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. |
title_short |
A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. |
title_full |
A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. |
title_fullStr |
A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. |
title_full_unstemmed |
A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. |
title_sort |
high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2017 |
url |
https://doi.org/10.1371/journal.pntd.0005373 https://doaj.org/article/5bea801b8d2341d98b24fb6b54aadb52 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 11, Iss 2, p e0005373 (2017) |
op_relation |
http://europepmc.org/articles/PMC5310922?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005373 https://doaj.org/article/5bea801b8d2341d98b24fb6b54aadb52 |
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https://doi.org/10.1371/journal.pntd.0005373 |
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PLOS Neglected Tropical Diseases |
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e0005373 |
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