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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 and more successful treatments for leishmaniasis. A novel method has been devised to study the metabolome and lipidome of<jats:named-content content-type=\"genus-species\">Leishmania donovani<\/jats:named-content>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.<jats:named-content content-type=\"genus-species\">Leishmania major<\/jats:named-content>promastigotes devoid of SL biosynthesis through loss of the serine palmitoyl transferase gene (\u0394LCB2) were 3-fold less sensitive to miltefosine than wild-type (WT) parasites. Changes in the metabolome and lipidome of miltefosine-treated<jats:named-content content-type=\"genus-species\">L. major<\/jats:named-content>mirrored those of<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>. A lack of SLs in the \u0394LCB2 mutant was matched by substantial alterations in sterol content. Together, these data indicate that SLs and ergosterol are important for miltefosine sensitivity and, perhaps, MoA.<\/jats:p>","DOI":"10.1128\/aac.02095-17","type":"journal-article","created":{"date-parts":[[2018,2,15]],"date-time":"2018-02-15T10:08:11Z","timestamp":1518689291000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":42,"title":["Complex Interplay between Sphingolipid and Sterol Metabolism Revealed by Perturbations to the Leishmania Metabolome Caused by Miltefosine"],"prefix":"10.1128","volume":"62","author":[{"given":"Emily G.","family":"Armitage","sequence":"first","affiliation":[{"name":"Centre for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Campus Montepr\u00edncipe, Boadilla del Monte, Madrid, Spain"},{"name":"GSK I+D Diseases of the Developing World (DDW), Parque Tecnol\u00f3gico de Madrid, Tres Cantos, Madrid, Spain"},{"name":"Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences &amp; Glasgow Polyomics, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amjed Q. 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