Complex Interplay between Sphingolipid and Sterol Metabolism Revealed by Perturbations to the Leishmania Metabolome Caused by Miltefosine.
Complex Interplay between Sphingolipid and Sterol Metabolism Revealed by Perturbations to the Leishmania Metabolome Caused by Miltefosine.
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DOI：
10.1128/aac.02095-17
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发表时间：
2018-05
影响因子：
4.9
通讯作者：
Barbas C
中科院分区：
文献类型：
--
作者：
Armitage EG;Alqaisi AQI;Godzien J;Peña I;Mbekeani AJ;Alonso-Herranz V;López-Gonzálvez Á;Martín J;Gabarro R;Denny PW;Barrett MP;Barbas C
据世界卫生组织报告，每年有30 000多人死亡，200 000至400 000例新病例，内脏利什曼病是一种严重的疾病，影响着世界上一些最贫穷的人。随着耐药性的不断上升，改善治疗的需求巨大。米替福新仍然是治疗利什曼病的主要方法之一，但其作用方式（MoA）仍然未知。了解这种药物的MoA和寄生虫对治疗的反应可以帮助为新的和更成功的治疗利什曼病铺平道路。本研究设计了一种新的方法来研究米替福新对杜氏利什曼原虫无鞭毛体代谢组和脂质组的影响。米替福新引起了许多膜磷脂（PL）的急剧下降，除了氨基酸池，而鞘脂（SL）和甾醇增加。由于丝氨酸棕榈酰转移酶基因（Δ LCB 2）缺失而缺乏SL生物合成的主要利什曼原虫前鞭毛体对米替福新的敏感性比野生型（WT）寄生虫低3倍。米替膦处理L.主要反映了L。donovani。Δ LCB 2突变体中SL的缺乏与甾醇含量的实质性改变相匹配。总之，这些数据表明，SL和麦角固醇是重要的米替福新的敏感性，也许，MoA。
With the World Health Organization reporting over 30,000 deaths and 200,000 to 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 and 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 wild-type (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 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.