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

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 PMM res...

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Bibliographic Details
Published in:Microorganisms (Basel) 2021-07, Vol.9 (8), p.1546
Main Authors: Hendrickx, Sarah, Reis-Cunha, João Luís, Forrester, Sarah, Jeffares, Daniel C, Caljon, Guy
Format: Article
Language:English
Subjects:
Adenosine diphosphate
Adenosine triphosphate
Amastigotes
Aminoglycosides
ATP
Bioinformatics
Chromosomes
Cloning
CNV
Copy number
Drug resistance
Elongation
Gene sequencing
Genes
Genetic engineering
Genomes
Genomics
Kinases
Leishmania
Leishmania donovani
Mitochondria
Molecular modelling
Mutation
Nucleotides
Parasites
Paromomycin
Population
Proteasomes
Protein kinase
Protein transport
Protein-tyrosine-phosphatase
Proteins
resistance
RNA-binding protein
rRNA
sequencing
Single-nucleotide polymorphism
SNP
Translation
Tyrosine
Variation
Vector-borne diseases
Virulence
Visceral leishmaniasis
Whole genome sequencing
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Summary: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 PMM resistance have been identified so far. To gain insights into potential resistance mechanisms, twelve experimentally selected 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 ( , ), virulence ( ), mitochondrial function ( ), signaling ( , and ) and vesicular trafficking ( ). These results indicate that, in , the aminoglycoside PMM affects protein translational processes and underlines the complex and probably multifactorial origin of resistance.
ISSN:2076-2607
2076-2607
DOI:10.3390/microorganisms9081546