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

Clos, Joachim; Adaui, Vanessa; Tejera Nevado, Paloma; Schäfer, Carola; Schmidt, Sonja; Arévalo Zelada, Jorge Luis; Dujardin, Jean-Claude; Nühs, Andrea; Maes, Louis; Zander, Dorothea; Trübe, Leona

dc.contributor.author	Nühs, Andrea
dc.contributor.author	Schäfer, Carola
dc.contributor.author	Zander, Dorothea
dc.contributor.author	Trübe, Leona
dc.contributor.author	Tejera Nevado, Paloma
dc.contributor.author	Schmidt, Sonja
dc.contributor.author	Arévalo Zelada, Jorge Luis
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	2014
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.ispartofseries	International Journal for Parasitology: Drugs and Drug Resistance
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#3.03.07
dc.subject.ocde	https://purl.org/pe-repo/ocde/ford#3.01.05
dc.relation.issn	2211-3207