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...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-11-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001204&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849736245773598720 |
|---|---|
| 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 |
| collection | DOAJ |
| 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 |
| id | doaj-art-8f3e95995c734e62a7d35c0a2ca33da7 |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2010-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-8f3e95995c734e62a7d35c0a2ca33da72025-08-20T03:07:20ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742010-11-01611e100120410.1371/journal.ppat.1001204A molecular mechanism for eflornithine resistance in African trypanosomes.Isabel M VincentDarren CreekDavid G WatsonMohammed A KamlehDebra J WoodsPui Ee WongRichard J S BurchmoreMichael P BarrettHuman 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001204&type=printable |
| spellingShingle | 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. PLoS Pathogens |
| title | 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_short | A molecular mechanism for eflornithine resistance in African trypanosomes. |
| title_sort | molecular mechanism for eflornithine resistance in african trypanosomes |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001204&type=printable |
| work_keys_str_mv | AT isabelmvincent amolecularmechanismforeflornithineresistanceinafricantrypanosomes AT darrencreek amolecularmechanismforeflornithineresistanceinafricantrypanosomes AT davidgwatson amolecularmechanismforeflornithineresistanceinafricantrypanosomes AT mohammedakamleh amolecularmechanismforeflornithineresistanceinafricantrypanosomes AT debrajwoods amolecularmechanismforeflornithineresistanceinafricantrypanosomes AT puieewong amolecularmechanismforeflornithineresistanceinafricantrypanosomes AT richardjsburchmore amolecularmechanismforeflornithineresistanceinafricantrypanosomes AT michaelpbarrett amolecularmechanismforeflornithineresistanceinafricantrypanosomes AT isabelmvincent molecularmechanismforeflornithineresistanceinafricantrypanosomes AT darrencreek molecularmechanismforeflornithineresistanceinafricantrypanosomes AT davidgwatson molecularmechanismforeflornithineresistanceinafricantrypanosomes AT mohammedakamleh molecularmechanismforeflornithineresistanceinafricantrypanosomes AT debrajwoods molecularmechanismforeflornithineresistanceinafricantrypanosomes AT puieewong molecularmechanismforeflornithineresistanceinafricantrypanosomes AT richardjsburchmore molecularmechanismforeflornithineresistanceinafricantrypanosomes AT michaelpbarrett molecularmechanismforeflornithineresistanceinafricantrypanosomes |