Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure

Maya Berg, Manu Vanaerschot, Andris Jankevics, Bart Cuypers, Ilse Maes, Sandip Mukherjee, Basudha Khanal, Suman Rijal, Syamal Roy, Fred Opperdoes, Rainer Breitling, Jean Claude Dujardin

    Research output: Contribution to journalArticlepeer-review


    Summary: 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 SbIII drug pressure. © 2013 John Wiley & Sons Ltd.
    Original languageEnglish
    Pages (from-to)428-442
    Number of pages14
    JournalMolecular Microbiology
    Issue number2
    Publication statusPublished - Oct 2013


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