Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

Abstract

Antimony (SbIII) and miltefosine (MIL) are important drugs for the treatment of Leishmania parasite infections. The mitochondrion is likely to play a central role in SbIII and MIL induced cell death in this parasite. Enriched mitochondrial samples from Leishmania promastigotes selected step by step for in vitro resistance to SbIII and MIL were subjected to differential proteomic analysis. A shared decrease in both mutants in the levels of pyruvate dehydrogenase, dihydrolipoamide dehydrogenase, and isocitrate dehydrogenase was observed, as well as a differential abundance in two calcium-binding proteins and the unique dynamin-1-like protein of the parasite. Both mutants presented a shared increase in the succinyl-CoA:3-ketoacid-coenzyme A transferase and the abundance of numerous hypothetical proteins was also altered in both mutants. In general, the proteomic changes observed in the MIL mutant were less pronounced than in the SbIII mutant, probably due to the early appearance of a mutation in the miltefosine transporter abrogating the need for a strong mitochondrial adaptation. This study is the first analysis of the Leishmania mitochondrial proteome and offers powerful insights into the adaptations to this organelle during SbIII and MIL drug resistance.

Microbial Antimony Biogeochemistry: Enzymes, Regulation, and Related Metabolic Pathways

“…The proteomics analysis in Leishmania spp. showed that its mechanism of antimony resistance is complex, incorporating aspects of protein folding/chaperones, stress response, antioxidant/detoxification, diverse metabolic processes, RNA/DNA processing, and de novo protein biosynthesis (135)(136)(137)(138). The proteomic study of A. tumefaciens GW4 revealed that Sb(III) could influence the Ars resistance, the Sb(III) oxidase AnoA, phosphate metabolism, carbohydrate transport and metabolism, and the metabolism of lipids, purines, and amino acids ( Table 1).…”

“…(135)(136)(137)(138), Miscanthus sinensis (139), and Agrobacterium tumefaciens (117). The proteomics analysis in Leishmania spp.…”

Differential Metabolic Pathway Analysis of the Proteomes of Leishmania donovani and Leptomonas seymouri

“…Pyruvate is the master carbon fuel input supporting overall citric acid cycle carbon flux. Pyruvate dysmetabolism has been known to indicate resistance .…”

Differentially modulated proteins associated with Leishmaniasis—a systematic review of in-vivo and in-vitro studies

“…They also reported 42 proteins of several important pathways upregulated in antimonial resistant promastigotes, including trypanosome thiol synthesis and sterol biosynthesis. For the first time, Vincent et al [ 64 ] compared the mitochondrial proteomic profile of antimony resistant L. infantum promastigote with the wild type. Out of 28 DMP reported in the drug-resistant parasite, only ten proteins were up-regulating.…”