Summary of Study ST001238

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 PR000829. The data can be accessed directly via it's Project DOI: 10.21228/M8HX2M This work is supported by NIH grant, U2C- DK119886.

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

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST001238
Study TitleP falciparum asexual metabolomics following drug treatment (part-I)
Study SummaryP falciparum infected human red blood cells were treated with 10X IC50 drug for 2.5 hours, followed by extraction and analysis of polar metabolites using HPLC-MS or HPLC-MS/MS
Institute
Pennsylvania State University
Last NameLlinás
First NameManuel
AddressW126 Millennium Science Complex, University Park, PENNSYLVANIA, 16802, USA
Emailmul27@psu.edu
Phone(814) 867-3527
Submit Date2019-08-08
Raw Data AvailableYes
Raw Data File Type(s)mzXML
Analysis Type DetailLC-MS
Release Date2019-09-23
Release Version1
Manuel Llinás Manuel Llinás
https://dx.doi.org/10.21228/M8HX2M
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR000829
Project DOI:doi: 10.21228/M8HX2M
Project Title:Antimalarial pantothenamide metabolites target acetyl-CoA biosynthesis in Plasmodium falciparum
Project Summary:Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report the discovery of potent pantothenamide bioisosteres that are active against blood-stage Plasmodium falciparum parasites and that block transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties and cleared parasites in a humanized mouse infection model of P. falciparum. Metabolomics revealed that CoA biosynthetic enzymes converted pantothenamides into CoA-analogs that interfered with parasite acetyl-CoA anabolism. In vitro generated resistant parasites showed mutations in acetyl-CoA synthetase and acyl-CoA synthetase 11. Introduction and reversion of these mutations in P. falciparum by CRISPR/Cas9 gene editing confirmed the key roles of these enzymes in the sensitivity of the malaria parasite to pantothenamides. These pantothenamide compounds with a unique mode of action may have potential as drugs against malaria parasites.
Institute:Pennsylvania State University
Last Name:Llinás
First Name:Manuel
Address:W126 Millennium Science Complex, University Park, PENNSYLVANIA, 16802, USA
Email:mul27@psu.edu
Phone:(814) 867-3527
Publications:https://stm.sciencemag.org/content/11/510/eaas9917 DOI: 10.1126/scitranslmed.aas9917

Subject:

Subject ID:SU001306
Subject Type:Cultured cells
Subject Species:Plasmodium falciparum
Taxonomy ID:5833

Factors:

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

mb_sample_id local_sample_id Treatment
SA089885017_3CXP18.6-017
SA089886017_2CXP18.6-017
SA089887017_1CXP18.6-017
SA089888026_2CXP18.6-026
SA089889026_3CXP18.6-026
SA089890026_1CXP18.6-026
SA089891052_3CXP18.6-052
SA089892052_2CXP18.6-052
SA089893052_1CXP18.6-052
SA089894258_3MMV689258
SA089895258_2MMV689258
SA089896258_1MMV689258
SA089897ND_2None
SA089898ND_1None
SA089899ND_3aNone
SA089900ND_1aNone
SA089901ND_2aNone
SA089902ND_3None
Showing results 1 to 18 of 18

Collection:

Collection ID:CO001300
Collection Summary:For asexual metabolomics studies all parasites were grown in standard RPMI1640 containing ~1μM pantothenic acid and supplemented with 0.25% Albumax II (Gibco). 3D7 was cultured and magnetically purified using a MACS column.
Sample Type:Plasmodium cells

Treatment:

Treatment ID:TR001321
Treatment Summary:Briefly, trophozoite stage 3D7 parasites were magnetically purified, allowed to recover in RPMI1640 (0.25% Albumax II) at 0.4% parasitemia (1x10^8 cells/sample), and treated with drug (10X IC50) for 2.5 hours.

Sample Preparation:

Sampleprep ID:SP001314
Sampleprep Summary:Following treatment parasites were pelleted, washed with 1 mL of ice-cold 1X PBS, and extracted using 1 mL of ice-cold 9:1 MeOH:Water, containing the internal standard 13C4,15N1-Aspartate. Supernatants were clarified before drying under nitrogen, followed by resuspension in HPLC grade water containing 1 µM chlorpropamide to 1x10^6 parasites/µL for HPLC-MS analysis. 10 µL was injected on a Thermo Exactive Plus Orbitrap mass spectrometer for HPLC-MS-based targeted metabolomics (modified from Lu W et al 2010).

Combined analysis:

Analysis ID AN002056 AN002057
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Dionex Ultimate 3000 Shimadzu Prominence 20 UFLCXR
Column Phenomenex Synergi Hydro RP 100 A (100 x 2mm,2.5um) Waters Acquity BEH C18 (100 x 2mm,1.7um)
MS Type ESI ESI
MS instrument type Orbitrap Triple TOF
MS instrument name Thermo Q Exactive Plus Orbitrap ABI Sciex 5600 TripleTOF
Ion Mode NEGATIVE NEGATIVE
Units Fold change versus untreated Intensity

Chromatography:

Chromatography ID:CH001495
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Phenomenex Synergi Hydro RP 100 A (100 x 2mm,2.5um)
Chromatography Type:Reversed phase
  
Chromatography ID:CH001496
Instrument Name:Shimadzu Prominence 20 UFLCXR
Column Name:Waters Acquity BEH C18 (100 x 2mm,1.7um)
Chromatography Type:Reversed phase

MS:

MS ID:MS001908
Analysis ID:AN002056
Instrument Name:Thermo Q Exactive Plus Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Data was centroided to .mzXML for analysis in mzMine and Maven
Ion Mode:NEGATIVE
  
MS ID:MS001909
Analysis ID:AN002057
Instrument Name:ABI Sciex 5600 TripleTOF
Instrument Type:Triple TOF
MS Type:ESI
MS Comments:Data was centroided to .mzXML for analysis in mzMine and Maven
Ion Mode:NEGATIVE
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