Summary of project PR000809
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000809. The data can be accessed directly via it's Project DOI: 10.21228/M83X38 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR000809 |
| Project DOI: | doi: 10.21228/M83X38 |
| Project Title: | System-wide biochemical analysis reveals ozonide and artemisinin antimalarials initially act by disrupting malaria parasite haemoglobin digestion |
| Project Summary: | Artemisinins are currently the first-line antimalarials, and rely on a peroxide pharmacophore for their potent activity. OZ277 (arterolane) and OZ439 (artefenomel) are newer synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a “multi-omics” workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of peroxide-treated P. falciparum infected red blood cells (iRBCs) revealed a rapid depletion of short Hb-derived peptides, while untargeted peptidomics showed accumulation of longer Hb peptides. Quantitative proteomics and ABPP assays demonstrated that Hb digesting proteases were significantly increased in abundance and activity following treatment, respectively. The association between peroxide activity and Hb catabolism was also confirmed in a K13-mutant artemisinin resistant parasite line. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in peroxide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short peroxide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate peroxide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage peroxide-induced damage. |
| Institute: | Monash University |
| Last Name: | Giannangelo |
| First Name: | Carlo |
| Address: | 381 Royal Parade, Parkville, Victoria, 3052, Australia |
| Email: | carlo.giannangelo@monash.edu |
| Phone: | 99039282 |
Summary of all studies in project PR000809
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST001201 | Peroxide antimalarial treatment timecourse on trophozoite-stage P. falciparum parasites | Plasmodium falciparum;Homo sapiens | Monash University | MS | 2019-07-17 | 1 | 192 | Uploaded data (24G)* |
| ST001202 | Peroxide antimalarial treatment timecourse on ring-stage P. falciparum parasites | Plasmodium falciparum;Homo sapiens | Monash University | MS | 2019-07-17 | 1 | 135 | Uploaded data (11.5G)* |
| ST001204 | Peroxide antimalarial extended treatment timecourse on trophozoite-stage P. falciparum parasites | Plasmodium falciparum;Homo sapiens | Monash University | MS | 2019-07-17 | 1 | 96 | Uploaded data (9.7G)* |
| ST001205 | Peroxide antimalarial treatment of K13-mutant and -wildtype P. falciparum parasites | Plasmodium falciparum;Homo sapiens | Monash University | MS | 2019-07-17 | 1 | 28 | Uploaded data (2.4G)* |
