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

Armitage, E.G.; Alqaisi, A.Q.I.; Godzien, J.; Pena, I.; Mbekeani, A.J.; Alsonso-Herranz, V.; Lopez-Gonzalvez, A.; Martin, J.; Gabarro, R.; Denny, P.W.; Barrett, M.P.; Barbas, C.

doi:10.1128/aac.02095-17

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

Armitage, E.G.; Alqaisi, A.Q.I.; Godzien, J.; Pena, I.; Mbekeani, A.J.; Alsonso-Herranz, V.; Lopez-Gonzalvez, A.; Martin, J.; Gabarro, R.; Denny, P.W.; Barrett, M.P.; Barbas, C.

Authors

E.G. Armitage

A.Q.I. Alqaisi

J. Godzien

I. Pena

A.J. Mbekeani

V. Alsonso-Herranz

A. Lopez-Gonzalvez

J. Martin

R. Gabarro

Professor Paul Denny p.w.denny@durham.ac.uk
Professor

M.P. Barrett

C. Barbas

Abstract

With the World Health Organization reporting over 30,000 deaths and 200-400,000 new cases annually, visceral Leishmaniasis 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 Leishmaniasis, 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 Leishmaniasis. A novel method has been devised to study the metabolome and lipidome of Leishmania donovani 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. Leishmania major 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 L. major mirrored those of L. donovani. 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.

Citation

Armitage, E., Alqaisi, A., Godzien, J., Pena, I., Mbekeani, A., Alsonso-Herranz, V., …Barbas, C. (2018). A 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. https://doi.org/10.1128/aac.02095-17

Journal Article Type	Article
Acceptance Date	Jan 21, 2018
Online Publication Date	Feb 20, 2018
Publication Date	May 1, 2018
Deposit Date	Nov 27, 2017
Publicly Available Date	Mar 7, 2018
Journal	Antimicrobial Agents and Chemotherapy
Print ISSN	0066-4804
Electronic ISSN	1098-6596
Publisher	American Society for Microbiology
Peer Reviewed	Peer Reviewed
Volume	62
Issue	5
Article Number	e02095-17
Pages	e02095-17
DOI	https://doi.org/10.1128/aac.02095-17

Files

Accepted Journal Article (2.5 Mb)
PDF

Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
© 2018 Armitage et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.