Comparative high-throughput analysis of the Trypanosoma cruzi response to organometallic compounds.

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 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 protein in treated parasites, with Pd-dppf-mpo having a stronger effect than Pt-dppf-mpo on the transcriptome. We further functionally categorized differentially expressed transcripts and identified cellular processes and pathways significantly impacted by treatment with the compounds. Targets 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 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.