Summary of study ST001205

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.

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Study IDST001205
Study TitlePeroxide antimalarial treatment of K13-mutant and -wildtype P. falciparum parasites
Study SummaryRed blood cells (RBCs) infected with trophozoite stage P. falciparum parasites (Cam3.IIR539T or Cam3.IIrev lines) at 4% parasitaemia and 2% haematocrit were treated with 100 nM of DHA, OZ277 or OZ439 for a duration of 1, 3 and 5 h, respectively. The K13-mutant artemisinin resistant parasite line used was Cam3.IIR539T. The K13-wildtype artemisinin sensitive parasite line used was Cam3.IIrev. The Samples treated with vehicle (DMSO) acted as the untreated control.
Institute
Monash University
Last NameGiannangelo
First NameCarlo
Address381 Royal Parade, Parkville, Victoria, 3052, Australia
Emailcarlo.giannangelo@monash.edu
Phone99039282
Submit Date2019-06-26
Raw Data AvailableYes
Raw Data File Type(s).raw
Analysis Type DetailLC-MS
Release Date2019-07-17
Release Version1
Carlo Giannangelo Carlo Giannangelo
https://dx.doi.org/10.21228/M83X38
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

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
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