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Steroidal Antimetabolites Protect Mice against Trypanosoma brucei
Trypanosoma brucei, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268410/ https://www.ncbi.nlm.nih.gov/pubmed/35807334 http://dx.doi.org/10.3390/molecules27134088 |
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author | Chaudhuri, Minu Singha, Ujjal K. Vanderloop, Boden H. Tripathi, Anuj Nes, W. David |
author_facet | Chaudhuri, Minu Singha, Ujjal K. Vanderloop, Boden H. Tripathi, Anuj Nes, W. David |
author_sort | Chaudhuri, Minu |
collection | PubMed |
description | Trypanosoma brucei, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt Acanthamoeba sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) that can equally target T. brucei. We found that CHT/ERGT inhibited cell growth in vitro, yielding EC(50) values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered T. brucei cell morphology and death rapidly within hours. Notably, in vivo ERGT/CHT protected mice infected with T. brucei, doubling their survival time following daily treatment for 8–10 days at 50 mg/kg or 100 mg/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development. |
format | Online Article Text |
id | pubmed-9268410 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92684102022-07-09 Steroidal Antimetabolites Protect Mice against Trypanosoma brucei Chaudhuri, Minu Singha, Ujjal K. Vanderloop, Boden H. Tripathi, Anuj Nes, W. David Molecules Article Trypanosoma brucei, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt Acanthamoeba sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) that can equally target T. brucei. We found that CHT/ERGT inhibited cell growth in vitro, yielding EC(50) values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered T. brucei cell morphology and death rapidly within hours. Notably, in vivo ERGT/CHT protected mice infected with T. brucei, doubling their survival time following daily treatment for 8–10 days at 50 mg/kg or 100 mg/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development. MDPI 2022-06-25 /pmc/articles/PMC9268410/ /pubmed/35807334 http://dx.doi.org/10.3390/molecules27134088 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Chaudhuri, Minu Singha, Ujjal K. Vanderloop, Boden H. Tripathi, Anuj Nes, W. David Steroidal Antimetabolites Protect Mice against Trypanosoma brucei |
title | Steroidal Antimetabolites Protect Mice against Trypanosoma brucei |
title_full | Steroidal Antimetabolites Protect Mice against Trypanosoma brucei |
title_fullStr | Steroidal Antimetabolites Protect Mice against Trypanosoma brucei |
title_full_unstemmed | Steroidal Antimetabolites Protect Mice against Trypanosoma brucei |
title_short | Steroidal Antimetabolites Protect Mice against Trypanosoma brucei |
title_sort | steroidal antimetabolites protect mice against trypanosoma brucei |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268410/ https://www.ncbi.nlm.nih.gov/pubmed/35807334 http://dx.doi.org/10.3390/molecules27134088 |
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