Abstract
The relatively high post-treatment relapse rates of paromomycin (PMM) in visceral leishmaniasis treatment and the swift emergence of experimental drug resistance challenge its broad application and urge for rational use and monitoring of resistance. However, no causal molecular mechanisms to Leishmania PMM resistance have been identified so far. To gain insights into potential resistance mechanisms, twelve experimentally selected Leishmania donovani clonal lines and the non-cloned preselection population, with variable degrees of PMM resistance, were subjected to whole genome sequencing. To identify genomic variations potentially associated with resistance, SNPs, Indels, chromosomal somy and gene copy number variations were compared between the different parasite lines. A total of 11 short nucleotide variations and the copy number alterations in 39 genes were correlated to PMM resistance. Some of the identified genes are involved in transcription, translation and protein turn-over (transcription elongation factor-like protein, RNA-binding protein, ribosomal protein L1a, 60S ribosomal protein L6, eukaryotic translation initiation factor 4E-1, proteasome regulatory non-ATP-ase subunit 3), virulence (major surface protease gp63, protein-tyrosine phosphatase 1-like protein), mitochondrial function (ADP/ATP mitochondrial carrier-like protein), signaling (phosphatidylinositol 3-related kinase, protein kinase putative and protein-tyrosine phosphatase 1-like protein) and vesicular trafficking (ras-related protein RAB1). These results indicate that, in Leishmania, the aminoglycoside PMM affects protein translational processes and underlines the complex and probably multifactorial origin of resistance.
Highlights
Leishmania parasites belong to the family of Trypanosomatidae and are unicellular flagellates that are transmitted between different vertebrates via the bites of infected sand flies
PMM resistance mechanisms are well-established for bacteria [28,29], several hypotheses have been postulated for Leishmania, such as interference with ribosomal protein synthesis and inhibition of respiration [11,30,31,32,33,34,35]
To try to identify these markers, the present study performed whole genome sequencing and comparison of 12 amastigote-selected clones and the pre-selection population, that had a large range of PMM resistances (Table 1)
Summary
Leishmania parasites belong to the family of Trypanosomatidae and are unicellular flagellates that are transmitted between different vertebrates via the bites of infected sand flies. Leishmania can cause either cutaneous (CL), mucocutaneous (MCL) or visceral leishmaniasis (VL). These parasites are known for their high plasticity and rapid adaptation to different environmental conditions, such as drug exposure [1]. The relatively high post-treatment relapse rates challenge the broad application of PMM in VL treatment, and urge for rational use and monitoring of the emergence of resistance [7], because several in vitro and in vivo laboratory studies demonstrated fairly easy selection of resistance both on promastigotes and intracellular amastigotes [8,9,10,11].
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