Complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine

Armitage, E. G. et al. (2018) Complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine. Antimicrobial Agents and Chemotherapy, 62(5), e02095-17. (doi:10.1128/AAC.02095-17) (PMID:29463533)

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Abstract

With the World Health Organization reporting over 30,000 deaths and 200-400,000 new cases annually, visceral sis is a serious disease affecting some of the world's poorest people. As drug resistance continues to rise, there is a huge unmet need to improve treatment. Miltefosine remains one of the main treatments for sis, yet its mode of action (MoA) is still unknown. Understanding the MoA of this drug and parasite response to treatment could help pave the way for new, more successful treatments for sis. A novel method has been devised to study the metabolome and lipidome of axenic amastigotes treated with miltefosine. Miltefosine caused a dramatic decrease in many membrane phospholipids (PLs), in addition to amino acid pools, while sphingolipids (SLs) and sterols increased. promastigotes devoid of SL biosynthesis through loss of the serine palmitoyl transferase gene (ΔLCB2) were 3-fold less sensitive to miltefosine than WT parasites. Changes in the metabolome and lipidome of miltefosine treated mirrored those of A lack of SLs in the ΔLCB2 was matched by substantial alterations in sterol content. Together these data indicate that SLs and ergosterol are important for miltefosine sensitivity and perhaps, MoA.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Armitage, Dr Emily Grace and Barrett, Professor Michael
Authors: Armitage, E. G., Alqaisi, A. Q.I., Godzien, J., Peña, I., Mbekeani, A. J., Alsonso-Herranz, V., López-Gonzálvez, Á., Martín, J., Gabarro, R., Denny, P. W., Barrett, M. P., and Barbas, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Antimicrobial Agents and Chemotherapy
Publisher:American Society for Microbiology
ISSN:0066-4804
ISSN (Online):1098-6596
Published Online:20 February 2018
Copyright Holders:Copyright © 2018 Armitage et al.
First Published:First published in Antimicrobial Agents and Chemotherapy 62(5):e02095-17
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY