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Article

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

1
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, Belgium
2
Department of Biology and York Biomedical Research Institute, University of York, York YO31 5DD, UK
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Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
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Academic Editor: José María Alunda
Microorganisms 2021, 9(8), 1546; https://doi.org/10.3390/microorganisms9081546
Received: 18 June 2021 / Revised: 12 July 2021 / Accepted: 13 July 2021 / Published: 21 July 2021
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. View Full-Text
Keywords: paromomycin; resistance; sequencing; SNP; CNV paromomycin; resistance; sequencing; SNP; CNV
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MDPI and ACS Style

Hendrickx, S.; Reis-Cunha, J.L.; Forrester, S.; Jeffares, D.C.; Caljon, G. Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms. Microorganisms 2021, 9, 1546. https://doi.org/10.3390/microorganisms9081546

AMA Style

Hendrickx S, Reis-Cunha JL, Forrester S, Jeffares DC, Caljon G. Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms. Microorganisms. 2021; 9(8):1546. https://doi.org/10.3390/microorganisms9081546

Chicago/Turabian Style

Hendrickx, Sarah, João Luís Reis-Cunha, Sarah Forrester, Daniel C. Jeffares, and Guy Caljon. 2021. "Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms" Microorganisms 9, no. 8: 1546. https://doi.org/10.3390/microorganisms9081546

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