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In vitro selection of miltefosine resistance in promastigotes of Leishmania donovani from Nepal: genomic and metabolomic characterization.

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Shaw, CD 
Lonchamp, J 
Downing, T 
Imamura, H 
Freeman, TM 


In this study, we followed the genomic, lipidomic and metabolomic changes associated with the selection of miltefosine (MIL) resistance in two clinically derived Leishmania donovani strains with different inherent resistance to antimonial drugs (antimony sensitive strain Sb-S; and antimony resistant Sb-R). MIL-R was easily induced in both strains using the promastigote-stage, but a significant increase in MIL-R in the intracellular amastigote compared to the corresponding wild-type did not occur until promastigotes had adapted to 12.2 μM MIL. A variety of common and strain-specific genetic changes were discovered in MIL-adapted parasites, including deletions at the LdMT transporter gene, single-base mutations and changes in somy. The most obvious lipid changes in MIL-R promastigotes occurred to phosphatidylcholines and lysophosphatidylcholines and results indicate that the Kennedy pathway is involved in MIL resistance. The inherent Sb resistance of the parasite had an impact on the changes that occurred in MIL-R parasites, with more genetic changes occurring in Sb-R compared with Sb-S parasites. Initial interpretation of the changes identified in this study does not support synergies with Sb-R in the mechanisms of MIL resistance, though this requires an enhanced understanding of the parasite's biochemical pathways and how they are genetically regulated to be verified fully.



Animals, Antimony, Antiprotozoal Agents, Drug Resistance, Female, Leishmania donovani, Leishmaniasis, Visceral, Lipid Metabolism, Membrane Transport Proteins, Mice, Mice, Inbred BALB C, Mutation, Nepal, Parasitic Sensitivity Tests, Phosphorylcholine

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Mol Microbiol

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Wellcome Trust (101239/Z/13/Z)
Biotechnology and Biological Sciences Research Council (BB/J014540/1)
This study was supported by as part of the FP7 EC K aladrug-R project (, grant number: 222895). JAC and MJS are supported by the Wellcome Trust via their core support for the Wellcome Trust Sanger Institute (grant number 098051) . TMF was funded by a BBSRC Research Experience Placement (grant number BB/J014540/1). CJRI was supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 101239/Z/13/Z). This research was supported in part by the National Science Foundation (grant number: NSF PHY11-25915) and by the Belgian Science Policy Office (TRIT, contract P7/41, to J-C.D.).