Different mutations in a p-type ATPase transporter in Leishmania parasites are associated with cross-resistance to two leading drugs by distinct mechanisms

Maes, L., Fernandez-Prada, C., Vincent, I. M. , Brotherton, M.-C., Roberts, M., Roy, G., Rivas, L., Leprohon, P., Smith, T. K. and Ouellette, M. (2016) Different mutations in a p-type ATPase transporter in Leishmania parasites are associated with cross-resistance to two leading drugs by distinct mechanisms. PLoS Neglected Tropical Diseases, 10(12), e0005171. (doi: 10.1371/journal.pntd.0005171) (PMID:27911896) (PMCID:PMC5135041)

Abstract

Leishmania infantum is an etiological agent of the life-threatening visceral form of leishmaniasis. Liposomal amphotericin B (AmB) followed by a short administration of miltefosine (MF) is a drug combination effective for treating visceral leishmaniasis in endemic regions of India. Resistance to MF can be due to point mutations in the miltefosine transporter (MT). Here we show that mutations in MT are also observed in Leishmania AmB-resistant mutants. The MF-induced MT mutations, but not the AmB induced mutations in MT, alter the translocation/uptake of MF. Moreover, mutations in the MT selected by AmB or MF have a major impact on lipid species that is linked to cross-resistance between both drugs. These alterations include changes of specific phospholipids, some of which are enriched with cyclopropanated fatty acids, as well as an increase in inositolphosphoceramide species. Collectively these results provide evidence of the risk of cross-resistance emergence derived from current AmB-MF sequential or co-treatments for visceral leishmaniasis.

• Item Type: Articles
• Additional Information: Work in TKS’s lab is supported by the Wellcome Trust grant 093228 and European Community’s Seventh Framework Programme under grant agreement No. 602773 (Project KINDRED). LR is supported by FEDER ISCIII PI12-02706 and RETICS (Ricet RD12/0018/0007). MO holds a Canada research chair in antimicrobial resistance and work in his lab is supported by the Canadian Institutes of Health Research (grant 15501).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Vincent, Dr Isabel
• Authors: Maes, L., Fernandez-Prada, C., Vincent, I. M., Brotherton, M.-C., Roberts, M., Roy, G., Rivas, L., Leprohon, P., Smith, T. K., and Ouellette, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS Neglected Tropical Diseases
• Publisher: Public Library of Science
• ISSN: 1935-2727
• ISSN (Online): 1935-2735
• Copyright Holders: Copyright © 2016 Fernandez-Prada et al.
• First Published: First published in PLoS Neglected Tropical Diseases 10(12): e0005171
• Publisher Policy: Reproduced under a Creative Commons license