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Comparative high-throughput analysis of the Trypanosoma cruzi response to organometallic compounds.
Metallomics ( IF 2.9 ) Pub Date : 2020-03-24 , DOI: 10.1039/d0mt00030b M Florencia Mosquillo 1 , Pablo Smircich , Martín Ciganda , Analía Lima , Dinorah Gambino , Beatriz Garat , Leticia Pérez-Díaz
Metallomics ( IF 2.9 ) Pub Date : 2020-03-24 , DOI: 10.1039/d0mt00030b M Florencia Mosquillo 1 , Pablo Smircich , Martín Ciganda , Analía Lima , Dinorah Gambino , Beatriz Garat , Leticia Pérez-Díaz
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There is an urgent need to develop new drugs against Chagas’ disease. In addition, the mechanisms of action of existing drugs have not been completely worked out at the molecular level. High throughput approaches have been demonstrated to be powerful tools not only for understanding the basic biology of Trypanosoma cruzi, but also for the identification of drug targets such as proteins or pathways that are essential for parasite infection and survival within the mammalian host. Here, we have applied these tools towards the discovery of the effects of two organometallic compounds with trypanocidal activity, Pd–dppf–mpo and Pt–dppf–mpo, on the transcriptome and proteome of T. cruzi epimastigotes. These approaches have not yet been reported for any other prospective metal-based anti T. cruzi drug. We found differentially expressed transcripts and proteins in treated parasites. Pd–dppf–mpo treatment resulted in more modulated transcripts (2327 of 10 785 identified transcripts) than Pt–dppf–mpo treatment (201 of 10 773 identified transcripts) suggesting a mechanism of action for Pd–dppf–mpo at the transcriptome level. Similar numbers of differentially expressed proteins (342 and 411 for Pd–dppf–mpo and Pt–dppf–mpo respectively) were also observed. We further functionally categorized differentially expressed transcripts and identified cellular processes and pathways significantly impacted by treatment with the compounds. Transcripts involved in DNA binding, protein metabolism, transmembrane transport, oxidative defense, and the ergosterol pathways were found to be modulated by the presence of the compounds. Our transcriptomic dataset also contained previously validated essential genes. These data allowed us to hypothesize a multimodal mechanism of action for the trypanocidal activity of Pd–dppf–mpo and Pt–dppf–mpo, and a differential contribution of the metal moiety of each compound.
中文翻译：
克氏锥虫对有机金属化合物的响应的高通量比较分析。
迫切需要开发抗南美锥虫病的新药。另外，现有药物的作用机理还没有在分子水平上完全阐明。高通量方法已被证明是强大的工具，不仅可用于了解克氏锥虫的基本生物学，而且可用于鉴定药物靶标，例如蛋白质或哺乳动物宿主内寄生虫感染和生存所必需的途径。在这里，我们将这些工具应用于发现具有锥虫杀灭活性的两种有机金属化合物，Pd-dppf-mpo和Pt-dppf-mpo对克鲁斯锥T的转录组和蛋白质组的影响。尚未针对其他任何潜在的基于金属的抗药性报道过这些方法克鲁斯药品。我们发现在处理过的寄生虫中差异表达的转录本和蛋白质。Pd–dppf–mpo处理比Pt–dppf–mpo处理（10,773鉴定出的笔录中的201）产生更多的调控转录本（在10 785个已鉴定的转录本中有2327个），表明Pd–dppf–mpo在转录组水平上具有作用机制。还观察到了相似数量的差异表达蛋白（Pd–dppf–mpo和Pt–dppf–mpo分别为342和411）。我们进一步对差异表达的转录本进行功能分类，并确定了受化合物处理影响显着的细胞过程和途径。发现与DNA结合，蛋白质代谢，跨膜转运，氧化防御和麦角固醇途径有关的转录本受化合物存在的调节。我们的转录组数据集还包含先前已验证的必需基因。这些数据使我们能够推测Pd–dppf–mpo和Pt–dppf–mpo的锥虫杀虫活性的多峰作用机理，以及每种化合物的金属部分的不同贡献。
更新日期：2020-03-24
中文翻译：
克氏锥虫对有机金属化合物的响应的高通量比较分析。
迫切需要开发抗南美锥虫病的新药。另外，现有药物的作用机理还没有在分子水平上完全阐明。高通量方法已被证明是强大的工具，不仅可用于了解克氏锥虫的基本生物学，而且可用于鉴定药物靶标，例如蛋白质或哺乳动物宿主内寄生虫感染和生存所必需的途径。在这里，我们将这些工具应用于发现具有锥虫杀灭活性的两种有机金属化合物，Pd-dppf-mpo和Pt-dppf-mpo对克鲁斯锥T的转录组和蛋白质组的影响。尚未针对其他任何潜在的基于金属的抗药性报道过这些方法克鲁斯药品。我们发现在处理过的寄生虫中差异表达的转录本和蛋白质。Pd–dppf–mpo处理比Pt–dppf–mpo处理（10,773鉴定出的笔录中的201）产生更多的调控转录本（在10 785个已鉴定的转录本中有2327个），表明Pd–dppf–mpo在转录组水平上具有作用机制。还观察到了相似数量的差异表达蛋白（Pd–dppf–mpo和Pt–dppf–mpo分别为342和411）。我们进一步对差异表达的转录本进行功能分类，并确定了受化合物处理影响显着的细胞过程和途径。发现与DNA结合，蛋白质代谢，跨膜转运，氧化防御和麦角固醇途径有关的转录本受化合物存在的调节。我们的转录组数据集还包含先前已验证的必需基因。这些数据使我们能够推测Pd–dppf–mpo和Pt–dppf–mpo的锥虫杀虫活性的多峰作用机理，以及每种化合物的金属部分的不同贡献。
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