Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms.
Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms.
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DOI：
10.3390/microorganisms9081546
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发表时间：
2021-07-21
期刊：
影响因子：
4.5
通讯作者：
Caljon G
中科院分区：
文献类型：
--
作者：
Hendrickx S;Reis-Cunha JL;Forrester S;Jeffares DC;Caljon G
巴龙霉素（PMM）治疗内脏利什曼病后复发率较高，耐药性的迅速出现，使其应用受到挑战，迫切需要合理用药和监测耐药性。然而，到目前为止，尚未确定利什曼原虫PMM抗性的致病分子机制。为了深入了解潜在的耐药机制，12个实验选择的杜氏利什曼原虫克隆系和非克隆预选人口，与不同程度的PMM抗性，进行全基因组测序。为了鉴定可能与抗性相关的基因组变异，在不同寄生虫系之间比较了SNP、插入缺失、染色体体和基因拷贝数变异。共发现11个短核苷酸变异和39个基因的拷贝数改变与PMM抗性相关。一些已鉴定的基因参与转录、翻译和蛋白质周转（转录延伸因子样蛋白、RNA结合蛋白、核糖体蛋白L1 a、60 S核糖体蛋白L 6、真核生物翻译起始因子4 E-1、蛋白酶体调节非ATP酶亚基3）、毒力（主要表面蛋白酶gp 63，蛋白酪氨酸磷酸酶1样蛋白），线粒体功能（ADP/ATP线粒体载体样蛋白），信号传导（磷脂酰肌醇3相关激酶，蛋白激酶推定和蛋白酪氨酸磷酸酶1样蛋白）和囊泡运输（ras相关蛋白RAB 1）。这些结果表明，在利什曼原虫，氨基糖苷类PMM影响蛋白质的翻译过程，并强调了复杂的，可能是多因素的耐药起源。
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.
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影响因子：
6.4
作者：
Dumetz F;Imamura H;Sanders M;Seblova V;Myskova J;Pescher P;Vanaerschot M;Meehan CJ;Cuypers B;De Muylder G;Späth GF;Bussotti G;Vermeesch JR;Berriman M;Cotton JA;Volf P;Dujardin JC;Domagalska MA
通讯作者：
Domagalska MA
影响因子：
3.8
作者：
Hendrickx, Sarah;da Luz, Raquel Andrea Inocencio;Maes, Louis
通讯作者：
Maes, Louis
影响因子：
3.8
作者：
Hailu A;Musa A;Wasunna M;Balasegaram M;Yifru S;Mengistu G;Hurissa Z;Hailu W;Weldegebreal T;Tesfaye S;Makonnen E;Khalil E;Ahmed O;Fadlalla A;El-Hassan A;Raheem M;Mueller M;Koummuki Y;Rashid J;Mbui J;Mucee G;Njoroge S;Manduku V;Musibi A;Mutuma G;Kirui F;Lodenyo H;Mutea D;Kirigi G;Edwards T;Smith P;Muthami L;Royce C;Ellis S;Alobo M;Omollo R;Kesusu J;Owiti R;Kinuthia J;Leishmaniasis East Africa Platform (LEAP) group
通讯作者：
Leishmaniasis East Africa Platform (LEAP) group
影响因子：
3.7
作者：
Chawla, Bhavna;Jhingran, Anupam;Madhubala, Rentala
通讯作者：
Madhubala, Rentala
影响因子：
5.6
作者：
Grossman, Iris;Alon, Assaf;Fass, Deborah
通讯作者：
Fass, Deborah