Complex Interplay between Sphingolipid and Sterol Metabolism Revealed by Perturbations to the Leishmania Metabolome Caused by Miltefosine

Antimicrobial Agents and Chemotherapy
Emily G ArmitageCoral Barbas

Abstract

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 d...Continue Reading

References

Feb 15, 2001·International Journal of Radiation Oncology, Biology, Physics·G A RuiterW J van Blitterswijk
Dec 7, 2002·Molecular and Biochemical Parasitology·Rachel Zufferey, Choukri Ben Mamoun
Feb 26, 2004·Antimicrobial Agents and Chemotherapy·Caroline ParisJaqueline Bréard
Mar 9, 2004·Biochimica Et Biophysica Acta·Michaëlle RakotomangaMichèle Saint-Pierre-Chazalet
Apr 20, 2004·Drugs of Today·D E Gutstein, V Fuster
Jul 17, 2004·Molecular Microbiology·Paul W Denny, Deborah F Smith
Jul 16, 2005·Science·Alasdair C IvensPeter J Myler
Jan 24, 2007·Antimicrobial Agents and Chemotherapy·M RakotomangaP M Loiseau
May 15, 2009·The Journal of Biological Chemistry·Ilona DarlyukDan Zilberstein
Sep 15, 2009·The Journal of Antimicrobial Chemotherapy·M Saint-Pierre-ChazaletP M Loiseau
Dec 23, 2009·Molecular and Biochemical Parasitology·Kai Zhang, Stephen M Beverley
Jan 30, 2010·Parasitology·Richard A ScheltemaRainer Breitling
Dec 15, 2010·PLoS Neglected Tropical Diseases·Ruben t'KindtSaskia Decuypere
Dec 21, 2010·Amino Acids·Ehud InbarClaudio A Pereira
Dec 30, 2011·PLoS Neglected Tropical Diseases·Ana Marta SilvaGraham H Coombs
Jun 29, 2012·Electrophoresis·Gisele A B CanutoCoral Barbas
Dec 4, 2012·Nature Reviews. Microbiology·William R ProtoJeremy C Mottram
Apr 11, 2013·Antimicrobial Agents and Chemotherapy·Manu De RyckerDavid W Gray
Mar 7, 2014·International Journal for Parasitology. Drugs and Drug Resistance·Isabel M VincentMarc Ouellette
Apr 12, 2014·Analytical and Bioanalytical Chemistry·Gisele A B CanutoÁngeles López-Gonzálvez
Aug 12, 2014·The Lancet Global Health·Belen PedriqueJean-Hervé Bradol
Apr 5, 2016·PLoS Pathogens·Adele Goldman-PinkovichDan Zilberstein
May 11, 2016·Proceedings of the National Academy of Sciences of the United States of America·Élodie GazanionMarc Ouellette

❮ Previous
Next ❯

Citations

Nov 10, 2018·The Journal of Antimicrobial Chemotherapy·Eline EberhardtGuy Caljon
Nov 17, 2019·International Journal of Molecular Sciences·Rita CapelaFrancisca Lopes
Nov 30, 2019·Parasite : Journal De La Société Française De Parasitologie·John C Meade
Jul 1, 2020·Microorganisms·Magali Van den KerkhofGuy Caljon
Jul 19, 2019·Frontiers in Cellular and Infection Microbiology·Karina M RebelloClaudia M d'Avila-Levy
Jan 23, 2021·RSC Medicinal Chemistry·Orlagh AndersonPaul W Denny
Feb 3, 2021·Infection and Immunity·Adwaita R Parab, Laura-Isobel McCall
Jul 3, 2021·Biomedicines·Zemfira N KaramyshevaKai Zhang
Oct 19, 2019·Analytical Chemistry·Carolina González-RianoCoral Barbas

❮ Previous
Next ❯

Software Mentioned

MassHunter Profinder

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.

Barrett Esophagus

Barrett’s esophagus if a serious complication of gastroesophageal reflux disease during which the normal esophageal lining changes to tissue that resembles intestinal lining. Here is the latest research.

African Trypanosomiasis

African trypanosomiasis, also known as sleeping sickness, is an insect-borne parasitic disease of humans and other animals. It is caused by protozoa of the species Trypanosoma brucei and almost invariably progresses to death unless treated. Discover the latest research on African trypanosomiasis here.