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dc.contributor.authorMejia, AMen_US
dc.contributor.authorHall, BSen_US
dc.contributor.authorTaylor, MCen_US
dc.contributor.authorGómez-Palacio, Aen_US
dc.contributor.authorWilkinson, SRen_US
dc.contributor.authorTriana-Chávez, Oen_US
dc.contributor.authorKelly, JMen_US
dc.date.accessioned2016-05-18T12:19:56Z
dc.date.issued2012-07-15en_US
dc.date.submitted2016-04-21T16:26:50.195Z
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/12389
dc.description.abstractBenznidazole is the frontline drug used against Trypanosoma cruzi, the causative agent of Chagas disease. However, treatment failures are often reported. Here, we demonstrate that independently acquired mutations in the gene encoding a mitochondrial nitroreductase (TcNTR) can give rise to distinct drug-resistant clones within a single population. Following selection of benznidazole-resistant parasites, all clones examined had lost one of the chromosomes containing the TcNTR gene. Sequence analysis of the remaining TcNTR allele revealed 3 distinct mutant genes in different resistant clones. Expression studies showed that these mutant proteins were unable to activate benznidazole. This correlated with loss of flavin mononucleotide binding. The drug-resistant phenotype could be reversed by transfection with wild-type TcNTR. These results identify TcNTR as a central player in acquired resistance to benznidazole. They also demonstrate that T. cruzi has a propensity to undergo genetic changes that can lead to drug resistance, a finding that has implications for future therapeutic strategies.en_US
dc.description.sponsorshipThis work was supported by the Wellcome Trust (grant 084175 to J. M. K. and grant 082342 to S. R. W.), COLCIENCIAS (project 111551929168 to A. M. M. and O. T. C.), and a fellowship (to A. M. M.).en_US
dc.format.extent220 - 228en_US
dc.languageengen_US
dc.relation.ispartofJ Infect Disen_US
dc.rights© The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.subjectAllelesen_US
dc.subjectAmino Acid Sequenceen_US
dc.subjectAnimalsen_US
dc.subjectCercopithecus aethiopsen_US
dc.subjectCloning, Molecularen_US
dc.subjectDrug Resistanceen_US
dc.subjectGene Expression Regulationen_US
dc.subjectGenetic Variationen_US
dc.subjectMolecular Sequence Dataen_US
dc.subjectMutationen_US
dc.subjectNitroimidazolesen_US
dc.subjectNitroreductasesen_US
dc.subjectProtozoan Proteinsen_US
dc.subjectRatsen_US
dc.subjectTrypanocidal Agentsen_US
dc.subjectTrypanosoma cruzien_US
dc.subjectVero Cellsen_US
dc.titleBenznidazole-resistance in Trypanosoma cruzi is a readily acquired trait that can arise independently in a single population.en_US
dc.typeArticle
dc.identifier.doi10.1093/infdis/jis331en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/22551809en_US
pubs.issue2en_US
pubs.notesNot knownen_US
pubs.publication-statusPublisheden_US
pubs.volume206en_US


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