Affiliation:
1. Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
Abstract
ABSTRACT
The mechanisms underlying the drug resistance of
Leishmania
spp. are manifold and not completely identified. Apart from the highly conserved multidrug resistance gene family known from higher eukaryotes,
Leishmania
spp. also possess genus-specific resistance marker genes. One of them, ARM58, was first identified in
Leishmania braziliensis
using a functional cloning approach, and its domain structure was characterized in
L. infantum
. Here we report that
L. infantum
ARM58 is part of a gene cluster at the telomeric end of chromosome 34 also comprising the neighboring genes ARM56 and HSP23. We show that overexpression of all three genes can confer antimony resistance to intracellular amastigotes. Upon overexpression in
L. donovani
, ARM58 and ARM56 are secreted via exosomes, suggesting a scavenger/secretion mechanism of action. Using a combination of functional cloning and next-generation sequencing, we found that the gene cluster was selected only under antimonyl tartrate challenge and weakly under Cu
2+
challenge but not under sodium arsenite, Cd
2+
, or miltefosine challenge. The selective advantage is less pronounced in intracellular amastigotes treated with the sodium stibogluconate, possibly due to the known macrophage-stimulatory activity of this drug, against which these resistance markers may not be active. Our data point to the specificity of these three genes for antimony resistance.
Funder
European Union 7th Framework Programme
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
24 articles.
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