Experimental Selection of Paromomycin Resistance in <i>Leishmania donovani</i> 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 <i&g...
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MDPI AG
2021-07-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/9/8/1546 |
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| author | Sarah Hendrickx João Luís Reis-Cunha Sarah Forrester Daniel C. Jeffares Guy Caljon |
| author_facet | Sarah Hendrickx João Luís Reis-Cunha Sarah Forrester Daniel C. Jeffares Guy Caljon |
| author_sort | Sarah Hendrickx |
| collection | DOAJ |
| 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 <i>Leishmania</i> PMM resistance have been identified so far. To gain insights into potential resistance mechanisms, twelve experimentally selected <i>Leishmania donovani</i> 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 (<i>transcription elongation factor-like protein</i>, <i>RNA-binding protein, ribosomal protein L1a, 60S ribosomal protein L6, eukaryotic translation initiation factor 4E-1, proteasome regulatory non-ATP-ase subunit 3</i>), virulence (<i>major surface protease gp63, protein-tyrosine phosphatase 1-like protein</i>), mitochondrial function (<i>ADP/ATP mitochondrial carrier-like protein</i>), signaling (<i>phosphatidylinositol 3-related kinase</i>, <i>protein kinase putative</i> and <i>protein-tyrosine phosphatase 1-like protein</i>) and vesicular trafficking (<i>ras-related protein RAB1</i>). These results indicate that, in <i>Leishmania</i>, the aminoglycoside PMM affects protein translational processes and underlines the complex and probably multifactorial origin of resistance. |
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| language | English |
| last_indexed | 2024-03-10T08:35:43Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
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| series | Microorganisms |
| spelling | doaj.art-fcd24c9f5d754ac6be7f30ebcfe432cb2023-11-22T08:45:19ZengMDPI AGMicroorganisms2076-26072021-07-0198154610.3390/microorganisms9081546Experimental Selection of Paromomycin Resistance in <i>Leishmania donovani</i> Amastigotes Induces Variable Genomic PolymorphismsSarah Hendrickx0João Luís Reis-Cunha1Sarah Forrester2Daniel C. Jeffares3Guy Caljon4Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, BelgiumDepartment of Biology and York Biomedical Research Institute, University of York, York YO31 5DD, UKDepartment of Biology and York Biomedical Research Institute, University of York, York YO31 5DD, UKDepartment of Biology and York Biomedical Research Institute, University of York, York YO31 5DD, UKLaboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, BelgiumThe 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 <i>Leishmania</i> PMM resistance have been identified so far. To gain insights into potential resistance mechanisms, twelve experimentally selected <i>Leishmania donovani</i> 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 (<i>transcription elongation factor-like protein</i>, <i>RNA-binding protein, ribosomal protein L1a, 60S ribosomal protein L6, eukaryotic translation initiation factor 4E-1, proteasome regulatory non-ATP-ase subunit 3</i>), virulence (<i>major surface protease gp63, protein-tyrosine phosphatase 1-like protein</i>), mitochondrial function (<i>ADP/ATP mitochondrial carrier-like protein</i>), signaling (<i>phosphatidylinositol 3-related kinase</i>, <i>protein kinase putative</i> and <i>protein-tyrosine phosphatase 1-like protein</i>) and vesicular trafficking (<i>ras-related protein RAB1</i>). These results indicate that, in <i>Leishmania</i>, the aminoglycoside PMM affects protein translational processes and underlines the complex and probably multifactorial origin of resistance.https://www.mdpi.com/2076-2607/9/8/1546paromomycinresistancesequencingSNPCNV |
| spellingShingle | Sarah Hendrickx João Luís Reis-Cunha Sarah Forrester Daniel C. Jeffares Guy Caljon Experimental Selection of Paromomycin Resistance in <i>Leishmania donovani</i> Amastigotes Induces Variable Genomic Polymorphisms Microorganisms paromomycin resistance sequencing SNP CNV |
| title | Experimental Selection of Paromomycin Resistance in <i>Leishmania donovani</i> Amastigotes Induces Variable Genomic Polymorphisms |
| title_full | Experimental Selection of Paromomycin Resistance in <i>Leishmania donovani</i> Amastigotes Induces Variable Genomic Polymorphisms |
| title_fullStr | Experimental Selection of Paromomycin Resistance in <i>Leishmania donovani</i> Amastigotes Induces Variable Genomic Polymorphisms |
| title_full_unstemmed | Experimental Selection of Paromomycin Resistance in <i>Leishmania donovani</i> Amastigotes Induces Variable Genomic Polymorphisms |
| title_short | Experimental Selection of Paromomycin Resistance in <i>Leishmania donovani</i> Amastigotes Induces Variable Genomic Polymorphisms |
| title_sort | experimental selection of paromomycin resistance in i leishmania donovani i amastigotes induces variable genomic polymorphisms |
| topic | paromomycin resistance sequencing SNP CNV |
| url | https://www.mdpi.com/2076-2607/9/8/1546 |
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