A molecular mechanism for eflornithine resistance in African trypanosomes.

Human African trypanosomiasis, endemic to sub-Saharan Africa, is invariably fatal if untreated. Its causative agent is the protozoan parasite Trypanosoma brucei. Eflornithine is used as a first line treatment for human African trypanosomiasis, but there is a risk that resistance could thwart its use...

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Autores principales:	Isabel M Vincent, Darren Creek, David G Watson, Mohammed A Kamleh, Debra J Woods, Pui Ee Wong, Richard J S Burchmore, Michael P Barrett
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8f3e95995c734e62a7d35c0a2ca33da7
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spelling	oai:doaj.org-article:8f3e95995c734e62a7d35c0a2ca33da72021-11-18T06:05:16ZA molecular mechanism for eflornithine resistance in African trypanosomes.1553-73661553-737410.1371/journal.ppat.1001204https://doaj.org/article/8f3e95995c734e62a7d35c0a2ca33da72010-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21124824/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Human African trypanosomiasis, endemic to sub-Saharan Africa, is invariably fatal if untreated. Its causative agent is the protozoan parasite Trypanosoma brucei. Eflornithine is used as a first line treatment for human African trypanosomiasis, but there is a risk that resistance could thwart its use, even when used in combination therapy with nifurtimox. Eflornithine resistant trypanosomes were selected in vitro and subjected to biochemical and genetic analysis. The resistance phenotype was verified in vivo. Here we report the molecular basis of resistance. While the drug's target, ornithine decarboxylase, was unaltered in resistant cells and changes to levels of metabolites in the targeted polyamine pathway were not apparent, the accumulation of eflornithine was shown to be diminished in resistant lines. An amino acid transporter gene, TbAAT6 (Tb927.8.5450), was found to be deleted in two lines independently selected for resistance. Ablating expression of this gene in wildtype cells using RNA interference led to acquisition of resistance while expression of an ectopic copy of the gene introduced into the resistant deletion lines restored sensitivity, confirming the role of TbAAT6 in eflornithine action. Eflornithine resistance is easy to select through loss of a putative amino acid transporter, TbAAT6. The loss of this transporter will be easily identified in the field using a simple PCR test, enabling more appropriate chemotherapy to be administered.Isabel M VincentDarren CreekDavid G WatsonMohammed A KamlehDebra J WoodsPui Ee WongRichard J S BurchmoreMichael P BarrettPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 11, p e1001204 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Isabel M Vincent Darren Creek David G Watson Mohammed A Kamleh Debra J Woods Pui Ee Wong Richard J S Burchmore Michael P Barrett A molecular mechanism for eflornithine resistance in African trypanosomes.
description	Human African trypanosomiasis, endemic to sub-Saharan Africa, is invariably fatal if untreated. Its causative agent is the protozoan parasite Trypanosoma brucei. Eflornithine is used as a first line treatment for human African trypanosomiasis, but there is a risk that resistance could thwart its use, even when used in combination therapy with nifurtimox. Eflornithine resistant trypanosomes were selected in vitro and subjected to biochemical and genetic analysis. The resistance phenotype was verified in vivo. Here we report the molecular basis of resistance. While the drug's target, ornithine decarboxylase, was unaltered in resistant cells and changes to levels of metabolites in the targeted polyamine pathway were not apparent, the accumulation of eflornithine was shown to be diminished in resistant lines. An amino acid transporter gene, TbAAT6 (Tb927.8.5450), was found to be deleted in two lines independently selected for resistance. Ablating expression of this gene in wildtype cells using RNA interference led to acquisition of resistance while expression of an ectopic copy of the gene introduced into the resistant deletion lines restored sensitivity, confirming the role of TbAAT6 in eflornithine action. Eflornithine resistance is easy to select through loss of a putative amino acid transporter, TbAAT6. The loss of this transporter will be easily identified in the field using a simple PCR test, enabling more appropriate chemotherapy to be administered.
format	article
author	Isabel M Vincent Darren Creek David G Watson Mohammed A Kamleh Debra J Woods Pui Ee Wong Richard J S Burchmore Michael P Barrett
author_facet	Isabel M Vincent Darren Creek David G Watson Mohammed A Kamleh Debra J Woods Pui Ee Wong Richard J S Burchmore Michael P Barrett
author_sort	Isabel M Vincent
title	A molecular mechanism for eflornithine resistance in African trypanosomes.
title_short	A molecular mechanism for eflornithine resistance in African trypanosomes.
title_full	A molecular mechanism for eflornithine resistance in African trypanosomes.
title_fullStr	A molecular mechanism for eflornithine resistance in African trypanosomes.
title_full_unstemmed	A molecular mechanism for eflornithine resistance in African trypanosomes.
title_sort	molecular mechanism for eflornithine resistance in african trypanosomes.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/8f3e95995c734e62a7d35c0a2ca33da7
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A molecular mechanism for eflornithine resistance in African trypanosomes.

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