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A novel marker, ARM58, confers antimony resistance to Leishmania spp

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dc.contributor.author Nuhs, Andrea
dc.contributor.author Schafer, Carola
dc.contributor.author Zander, Dorothea
dc.contributor.author Trube, Leona
dc.contributor.author Tejera Nevado, Paloma
dc.contributor.author Schmidt, Sonja
dc.contributor.author Arevalo, Jorge
dc.contributor.author Adaui, Vanessa
dc.contributor.author Maes, Louis
dc.contributor.author Dujardin, Jean-Claude
dc.contributor.author Clos, Joachim
dc.date.accessioned 2020-06-10T18:11:33Z
dc.date.available 2020-06-10T18:11:33Z
dc.date.issued 2013
dc.identifier.uri https://hdl.handle.net/20.500.12866/7991
dc.description.abstract Protozoa of the Leishmania genus cause a variety of disease forms that rank at the top of the list of neglected tropical diseases. Anti-leishmanial drugs based on pentavalent antimony have been the mainstay of therapy for over 60 years and resistance against them is increasingly encountered in the field. The biochemical basis for this is poorly understood and likely diverse. No stringent correlation between genetic markers and antimony resistance has so far been shown, prompting us to use a functional cloning approach to identify markers of resistance. Using gene libraries derived from drug-resistant and drug-sensitive Leishmania braziliensis clinical isolates in a functional cloning strategy, we repeatedly selected one gene locus located on chromosome 20 whose amplification confers increased antimony (III) resistance in vitro to an otherwise sensitive L. braziliensis clone. The gene responsible for the effect encodes a previously hypothetical protein that we dubbed LbrARM58. It comprises four repeats of a domain of unknown function, DUF1935, one of them harbouring a potential trans-membrane domain. The gene is so far unique to the Leishmania genus, while a structurally related gene without antimony resistance functionality is also found in Trypanosoma spp. Overexpression of LbrARM58 also confers antimony resistance to promastigotes and intracellular amastigotes of the related species Leishmania infantum, indicating a conserved function in Old World and New World Leishmania species. Our results also show that in spite of their RNAi system, L. braziliensis promastigotes can serve as acceptor cells for episomally propagated cosmid libraries, at least for the initial stages of functional cloning efforts. en_US
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof urn:issn:2211-3207
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Antimony en_US
dc.subject Leishmania braziliensis en_US
dc.subject Resistance en_US
dc.title A novel marker, ARM58, confers antimony resistance to Leishmania spp en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1016/j.ijpddr.2013.11.004
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.00 es_PE


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