Abstract
Leishmania parasites efficiently develop resistance against several types of drugs including antimonials, the primary antileishmanial drug historically implemented. The resistance to antimonials is considered to be a major risk factor for effective leishmaniasis treatment. To detect biomarkers/biopatterns for the differentiation of antimony-resistant Leishmania strains, we employed untargeted global mass spectrometry to identify intracellular lipids present in antimony sensitive and resistant parasites before and after antimony exposure. The lipidomic profiles effectively differentiated the sensitive and resistant phenotypes growing with and without antimony pressure. Resistant phenotypes were characterized by significant downregulation of phosphatidylcholines, sphingolipid decrease, and lysophosphatidylcholine increase, while sensitive phenotypes were characterized by the upregulation of triglycerides with long-chain fatty acids and a tendency toward the phosphatidylethanolamine decrease. Our findings suggest that the changes in lipid composition in antimony-resistant parasites contribute to the physiological response conducted to combat the oxidative stress unbalance caused by the drug. We have identified several lipids as potential biomarkers associated with the drug resistance.
Highlights
Leishmania species are the causal agent of leishmaniasis, a complex tropical disease considered to be the second most epidemiologically important after malaria, with more than 12 million infected people, 0.9 to 1.6 million new cases, and 20,000 to 30,000 deaths each year [1,2]
It is expected that resistant parasites acquire phenotypic changes some of which can persist in the absence of the drug pressure while others can be only detected when the parasites are growing under antimony exposure
Our study demonstrates that the development of antimony resistance includes extensive and dynamic lipid remodeling
Summary
Leishmania species are the causal agent of leishmaniasis, a complex tropical disease considered to be the second most epidemiologically important after malaria, with more than 12 million infected people, 0.9 to 1.6 million new cases, and 20,000 to 30,000 deaths each year [1,2]. Leishmania adopts two different stages in the life cycle. The geographical distribution, coinfection, host immune response, and Leishmania species/strains involved are associated with a wide range of different clinical outcomes including cutaneous, mucocutaneous and visceral forms [3]. Pentavalent antimonials (SbV ) have been used as the main leishmaniasis treatment worldwide for more than six decades [4]. It is commonly accepted that SbV works as a prodrug being reduced to trivalent antimony (SbIII ). SbIII induces oxidative stress [5,6]; inhibits the glycolytic pathway and fatty acid β-oxidation [7]; interferes with the purine salvage pathway [8]; inhibits the DNA topoisomerase I [9]; and competes
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