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dc.contributor.authorShaw, C. D.
dc.contributor.authorLonchamp, J.
dc.contributor.authorDowning, T.
dc.contributor.authorImamura, H.
dc.contributor.authorFreeman, T. M.
dc.contributor.authorCotton, J. A.
dc.contributor.authorSanders, M.
dc.contributor.authorBlackburn, G.
dc.contributor.authorDujardin, J. C.
dc.contributor.authorRijal, S.
dc.contributor.authorKhanal, B.
dc.contributor.authorIllingworth, C. J. R.
dc.contributor.authorCoombs, G. H.
dc.contributor.authorCarter, K. C.
dc.date.accessioned2018-09-20T16:24:30Z
dc.date.available2018-09-20T16:24:30Z
dc.date.issued2016-02-09
dc.identifier.citationShaw, C. D. Lonchamp, J.; Downing, T.; Imamura, H.; Freeman, T. M.; Cotton, J. A.; Sanders, M.; Blackburn, G.; Dujardin, J. C.; Rijal, S.; Khanal, B.; Illingworth, C. J. R.; Coombs, G. H.; Carter, K. C. (2016). in vitro selection of miltefosine resistance in promastigotes of leishmania donovani from nepal: genomic and metabolomic characterization. Molecular Microbiology 99 (6), 1134-1148
dc.identifier.issn0950-382X
dc.identifier.urihttp://hdl.handle.net/10379/13882
dc.description.abstractIn this study, we followed the genomic, lipidomic and metabolomic changes associated with the selection of miltefosine (MIL) resistance in two clinically derived Leishmania donovani strains with different inherent resistance to antimonial drugs (antimony sensitive strain Sb-S; and antimony resistant Sb-R). MIL-R was easily induced in both strains using the promastigote-stage, but a significant increase in MIL-R in the intracellular amastigote compared to the corresponding wild-type did not occur until promastigotes had adapted to 12.2 M MIL. A variety of common and strain-specific genetic changes were discovered in MIL-adapted parasites, including deletions at the LdMT transporter gene, single-base mutations and changes in somy. The most obvious lipid changes in MIL-R promastigotes occurred to phosphatidylcholines and lysophosphatidylcholines and results indicate that the Kennedy pathway is involved in MIL resistance. The inherent Sb resistance of the parasite had an impact on the changes that occurred in MIL-R parasites, with more genetic changes occurring in Sb-R compared with Sb-S parasites. Initial interpretation of the changes identified in this study does not support synergies with Sb-R in the mechanisms of MIL resistance, though this requires an enhanced understanding of the parasite's biochemical pathways and how they are genetically regulated to be verified fully.
dc.publisherWiley-Blackwell
dc.relation.ispartofMolecular Microbiology
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Ireland
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/ie/
dc.subjectdrug-resistance
dc.subjectvisceral leishmaniasis
dc.subjectantimony-resistant
dc.subjectexpression analysis
dc.subjectkala-azar
dc.subjectmechanisms
dc.subjecttransporter
dc.subjectpopulation
dc.subjectmutations
dc.subjectsusceptibility
dc.titlein vitro selection of miltefosine resistance in promastigotes of leishmania donovani from nepal: genomic and metabolomic characterization
dc.typeArticle
dc.identifier.doi10.1111/mmi.13291
dc.local.publishedsourcehttps://onlinelibrary.wiley.com/doi/pdf/10.1111/mmi.13291
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