Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms

Sarah Hendrickx, João Luís Reis-Cunha, Sarah Forrester, Daniel C Jeffares, Guy Caljon

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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.

Original languageEnglish
Article number1546
Number of pages14
Issue number8
Early online date21 Jul 2021
Publication statusPublished - 21 Jul 2021

Bibliographical note

Funding Information:
Funding: This work was funded by the Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO: projects G051812N and 12I0317N), and research funds of the University of Antwerp (TT-ZAPBOF 33049 and TOP-BOF 35017). Sarah Forrester was supported by a Wellcome Seed Award in Science to Daniel Jeffares (208965/Z/17/Z). LMPH is a partner of the Excellence Centre ‘Infla-Med’ (www. uantwerpen.be/infla-med; accessed on 19 July 2021).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • CNV
  • Paromomycin
  • Resistance
  • Sequencing
  • SNP

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