Cargando…

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 Leishma...

Descripción completa

Detalles Bibliográficos
Autores principales: Hendrickx, Sarah, Reis-Cunha, João Luís, Forrester, Sarah, Jeffares, Daniel C., Caljon, Guy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398221/
https://www.ncbi.nlm.nih.gov/pubmed/34442625
http://dx.doi.org/10.3390/microorganisms9081546
_version_ 1783744786663997440
author Hendrickx, Sarah
Reis-Cunha, João Luís
Forrester, Sarah
Jeffares, Daniel C.
Caljon, Guy
author_facet Hendrickx, Sarah
Reis-Cunha, João Luís
Forrester, Sarah
Jeffares, Daniel C.
Caljon, Guy
author_sort Hendrickx, Sarah
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8398221
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-83982212021-08-29 Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms Hendrickx, Sarah Reis-Cunha, João Luís Forrester, Sarah Jeffares, Daniel C. Caljon, Guy Microorganisms Article 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. MDPI 2021-07-21 /pmc/articles/PMC8398221/ /pubmed/34442625 http://dx.doi.org/10.3390/microorganisms9081546 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hendrickx, Sarah
Reis-Cunha, João Luís
Forrester, Sarah
Jeffares, Daniel C.
Caljon, Guy
Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms
title Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms
title_full Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms
title_fullStr Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms
title_full_unstemmed Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms
title_short Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms
title_sort experimental selection of paromomycin resistance in leishmania donovani amastigotes induces variable genomic polymorphisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398221/
https://www.ncbi.nlm.nih.gov/pubmed/34442625
http://dx.doi.org/10.3390/microorganisms9081546
work_keys_str_mv AT hendrickxsarah experimentalselectionofparomomycinresistanceinleishmaniadonovaniamastigotesinducesvariablegenomicpolymorphisms
AT reiscunhajoaoluis experimentalselectionofparomomycinresistanceinleishmaniadonovaniamastigotesinducesvariablegenomicpolymorphisms
AT forrestersarah experimentalselectionofparomomycinresistanceinleishmaniadonovaniamastigotesinducesvariablegenomicpolymorphisms
AT jeffaresdanielc experimentalselectionofparomomycinresistanceinleishmaniadonovaniamastigotesinducesvariablegenomicpolymorphisms
AT caljonguy experimentalselectionofparomomycinresistanceinleishmaniadonovaniamastigotesinducesvariablegenomicpolymorphisms