Summary of Study ST001175

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 PR000787. The data can be accessed directly via it's Project DOI: 10.21228/M8Z97B This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

Perform statistical analysis  |  Show all samples  |  Show named metabolites  |  Download named metabolite data  
Download mwTab file (text)   |  Download mwTab file(JSON)   |  Download data files (Contains raw data)
Study IDST001175
Study TitleMulti-omics analysis demonstrates unique mode of action of a potent new antimalarial compound, JPC-3210, against Plasmodium falciparum
Study SummaryThe increasing incidence of antimalarial drug resistance to the first-line artemisinins, and their combination partner drugs, underpins an urgent need for new antimalarial drugs, ideally with a novel mechanism of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum, low cytotoxicity, potent in vivo efficacy against murine malaria, and favourable preclinical pharmacokinetics, including a lengthy plasma elimination half-life. This study demonstrates the application of a “multi-omics” workflow based on high resolution orbitrap mass spectrometry to investigate the impact of JPC-3210 on biochemical pathways within P. falciparum infected red blood cells. Metabolomics and peptidomics analysis revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a depletion in short hemoglobin-derived peptides, while peptidomics analysis showed a depletion in longer hemoglobin-derived peptides. In order to further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerisation assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerisation, about 10-fold less potent then the quinoline antimalarials. Furthermore, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature in comparison to other known antimalarials. Whilst JPC-3210 clustered closely with mefloquine in the metabolomics and proteomics analyses, a key differentiating signature for JPC-3210 was the significant enrichment of parasite proteins involved in regulation of translation. In conclusion, multi-omics studies using high resolution mass spectrometry revealed JPC-3210 to possess a unique mechanism of action involving inhibition of hemoglobin digestion, depletion of DNA replication and synthesis proteins, and elevation of regulators of protein translation. Importantly, this mechanism is distinct from currently-used antimalarials, suggesting that JPC-3210 warrants further investigation as a potentially useful new antimalarial agent.
Institute
Monash University
Last NameSiddiqui
First NameGhizal
Address381 Royal Parade, Parkville
Emailghizal.siddiqui@monash.edu
Phone99039282
Submit Date2019-04-25
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2019-05-15
Release Version1
Ghizal Siddiqui Ghizal Siddiqui
https://dx.doi.org/10.21228/M8Z97B
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:


Factors:

Subject type: Other; Subject species: Plasmodium falciparum (Factor headings shown in green)

mb_sample_id local_sample_id Condition
SA081519P_Aqm_1Aqm treated
SA081520P_Aqm_3Aqm treated
SA081521P_Aqm_2Aqm treated
SA081522P_Aqm_4Aqm treated
SA081523P_Atov_2Atov treated
SA081524P_Atov_4Atov treated
SA081525P_Atov_1Atov treated
SA081526P_Atov_3Atov treated
SA081527Blank_3Blank
SA081528Blank_2Blank
SA081529Blank_6Blank
SA081530Blank_1Blank
SA081531Blank_4Blank
SA081532Blank_5Blank
SA081533P_CQ_4CQ treated
SA081534P_CQ_3CQ treated
SA081535P_CQ_2CQ treated
SA081536P_CQ_1CQ treated
SA081537P_DHA_4DHA treated
SA081538P_DHA_3DHA treated
SA081539P_DHA_2DHA treated
SA081540P_DHA_1DHA treated
SA081541P_DMSO_6DMSO treated
SA081542P_DMSO_8DMSO treated
SA081543P_DMSO_7DMSO treated
SA081544P_DMSO_2DMSO treated
SA081545P_DMSO_3DMSO treated
SA081546P_DMSO_4DMSO treated
SA081547P_DMSO_5DMSO treated
SA081548P_JPC_3JPC treated
SA081549P_JPC_2JPC treated
SA081550P_JPC_1JPC treated
SA081551P_LF_1LF treated
SA081552P_LF_2LF treated
SA081553P_LF_4LF treated
SA081554P_LF_3LF treated
SA081555P_MQ_2MQ treated
SA081556P_MQ_1MQ treated
SA081557P_MQ_3MQ treated
SA081558P_MQ_4MQ treated
SA081559P_PYN_3PYN treated
SA081560P_PYN_4PYN treated
SA081561P_PYN_1PYN treated
SA081562P_PYN_2PYN treated
SA081563QC_P_6QC
SA081564QC_P_5QC
SA081565QC_P_3QC
SA081566QC_P_1QC
SA081567QC_P_2QC
SA081568QC_P_4QC
SA081569P_TQ_1TQ treated
SA081570P_TQ_2TQ treated
SA081571P_TQ_3TQ treated
SA081572P_TQ_4TQ treated
Showing results 1 to 54 of 54
  logo