Exploiting Knowledge on Leishmania Drug Resistance to Support the Quest for New Drugs  Aya Hefnawy, Maya Berg, Jean-Claude Dujardin, Géraldine De Muylder  Trends in Parasitology  Volume 33, Issue 3, Pages 162-174 (March 2017) DOI: 10.1016/j.pt.2016.11.003 Copyright © 2017 The Authors Terms and Conditions

Figure 1 The ‘Many-Roads-to-DR’ Concept. For a Figure360 author presentation of Figure 1, see http://dx.doi.org/10.1016/j.pt.2016.11.003#mmc1. Leishmania exploit several molecular strategies to reach the same result. Panel A: Aquaglyceroporin 1 (AQP1) is the main transporter for uptake of Sb(III) by the parasite; its expression can be reduced or abolished through subtelomeric deletions of chromosome 31 (chr 31), in the locus including AQP1 [56,57], mutations affecting key residues of AQP1 [57], indels in the coding sequence of AQP1, causing premature stop codons [20] and reduced transcription of AQP1, without detected genomic changes [53,54]. Panel B: ATP-binding cassette transporter (MRPA) is responsible for sequestration of antimony-thiol conjugates in a Leishmania intracellular organelle; its expression can be increased by episomal [7,58,59] or intrachromosomal [20] genomic amplification of the H-locus, increased somy of chromosome 23 (chr 23) that bears the H-locus [20], or by increased transcription [7,58,59,61]. Panel C: miltefosine transporter (MT) is involved in the uptake of miltefosine by the parasite; its expression can be reduced by a decrease in somy of chromosome 13 (chr 13) [38], subtelomeric deletions in chromosome 13, in the locus including MT [38], mutations affecting key residues of MT [36,38,44,76], indels in the coding sequence of MT causing premature stop codon [39] and reduction of transcription without detected genomic changes [38]. Figure360: an author presentation of Figure 1 Trends in Parasitology 2017 33, 162-174DOI: (10.1016/j.pt.2016.11.003) Copyright © 2017 The Authors Terms and Conditions