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

Shaw, C.D. et al. (2016) In vitro selection of miltefosine resistance in promastigotes of Leishmania donovani from Nepal: genomic and metabolomic characterization. Molecular Microbiology, 99(6), pp. 1134-1148. (doi: 10.1111/mmi.13291) (PMID:26713880) (PMCID:PMC4832254)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Blackburn, Dr Gavin and Illingworth, Dr Chris and Cotton, Professor James
• Authors: Shaw, C.D., Lonchamp, J., Downing, T., Imamura, H., Freeman, T.M., Cotton, J.A., Sanders, M., Blackburn, G., Dujardin, J.C., Rijal, S., Khanal, B., Illingworth, C.J.R., Coombs, G.H., and Carter, K.C.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research; College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Molecular Microbiology
• Publisher: Wiley
• ISSN: 0950-382X
• ISSN (Online): 1365-2958
• Published Online: 09 February 2016
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Molecular Microbiology 99(6): 1134-1148
• Publisher Policy: Reproduced under a Creative Commons license