title: Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure.
abstract: Antimonial (sodium stibogluconate, SSG) resistance and differentiation have been shown to be closely linked in Leishmania donovani, with SSG-resistant strains showing an increased capacity to generate infectious (metacyclic) forms. This is the first untargeted LC-MS metabolomics study which integrated both phenomena in one experimental design and provided insights into metabolic differences between three clinical L. donovani strains with a similar genetic background but different SSG-susceptibilities. We performed this analysis at different stages during promastigote growth and in the absence or presence of drug pressure. When comparing SSG-resistant and SSG-sensitive strains, a number of metabolic changes appeared to be constitutively present in all growth stages, pointing towards a clear link with SSG-resistance, whereas most metabolic changes were only detected in the stationary stage. These changes reflect the close intertwinement between SSG-resistance and an increased metacyclogenesis in resistant parasites. The metabolic changes suggest that SSG-resistant parasites have (i) an increased capacity for protection against oxidative stress; (ii) a higher fluidity of the plasma membrane; and (iii) a metabolic survival kit to better endure infection. These changes were even more pronounced in a resistant strain kept under Sb(III) drug pressure.
authors.affiliation: Unit of Molecular Parasitology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Maya
authors.initials: M
authors.lastname: Berg
authors.forename: Manu
authors.initials: M
authors.lastname: Vanaerschot
authors.forename: Andris
authors.initials: A
authors.lastname: Jankevics
authors.forename: Bart
authors.initials: B
authors.lastname: Cuypers
authors.forename: Ilse
authors.initials: I
authors.lastname: Maes
authors.forename: Sandip
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Basudha
authors.initials: B
authors.lastname: Khanal
authors.forename: Suman
authors.initials: S
authors.lastname: Rijal
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
authors.forename: Fred
authors.initials: F
authors.lastname: Opperdoes
authors.forename: Rainer
authors.initials: R
authors.lastname: Breitling
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
mesh_terms: D000222:Adaptation, Physiological; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002454:Cell Differentiation; D002462:Cell Membrane / Q000502:physiology; D002853:Chromatography, Liquid; D004351:Drug Resistance; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D007898:Leishmaniasis, Visceral / Q000469:parasitology; D013058:Mass Spectrometry; D008560:Membrane Fluidity; D055432:Metabolomics; D018384:Oxidative Stress; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D000981:Antiprotozoal Agents; D000967:Antimony Sodium Gluconate