Reduced Antimony Accumulation in ARM 58 - Overexpressing 1 Leishmania infantum 2 Running title : ARM 58 antimony resistance marker

17 Antimony-based drugs are still the mainstay of chemotherapy against Leishmania infections in 18 many endemic countries. Efficacy of antimonials has been compromised by increasing numbers of 19 resistant infections, the basis of which is not fully understood and likely involves multiple factors. 20 By using a functional cloning strategy he have recently identified a novel antimony resistance 21 marker, ARM58, from the parasite Leishmania braziliensis that protects the parasites against 22 antimony-based antileishmanial compounds. Here we show that the L. infantum homologue also 23 confers resistance against antimony but not against other anti-leishmanial drugs, and that its 24 function depends critically on one of four conserved domains of unknown function. This critical 25 domain requires at least two hydrophobic amino acids and is predicted to form a transmembrane 26 structure. Overexpression of ARM58 in antimony-exposed parasites reduces the intracellular Sb 27 accumulation by over 70% indicating a role for ARM58 in Sb extrusion pathways, but without 28 involvement of energy-dependent transporter proteins. 29 on July 7, 2017 by gest httpaac.asm .rg/ D ow nladed fom