Summary of Study ST001652

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 PR001058. The data can be accessed directly via it's Project DOI: 10.21228/M8XX2B 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 IDST001652
Study TitleAtypical Molecular Basis for Drug Resistance to Mitochondrial AQ: A Function Inhibitors in Plasmodium falciparum
Study SummaryIn this study, we present a clear genotype for the P. falciparum SB1-A6 acridone-resistant clonal parasite strain and, through a combination of targeted and whole-cell methods, establish that the mechanism of resistance to both cytochrome bc1 and DHODH inhibitors results from the contribution of multiple genetic polymorphisms. We find that P. falciparum SB1-A6 accumulates both a copy number variation and a specific mutation in PfDHODH, and both of these genetic polymorphisms contribute to the panresistant phenotype. This study uncovers a mechanism of cross-resistance between PfDHODH and mtETC inhibitors and serves as a cautionary note to future antimalarial combination therapy formulations containing such drugs.
Institute
U.S. Food & Drug Administration
Last NamePainter
First NameHeather
Address10903 New Hampshire Ave., WO 52/72-5324, Silver Spring, MD 20993
EmailHeather.Painter@fda.hhs.gov
Phone240-402-2040
Submit Date2021-01-17
PublicationsDOI:10.1128/AAC.02143-20
Raw Data AvailableYes
Raw Data File Type(s)mzXML
Analysis Type DetailLC-MS
Release Date2021-02-01
Release Version1
Heather Painter Heather Painter
https://dx.doi.org/10.21228/M8XX2B
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001058
Project DOI:doi: 10.21228/M8XX2B
Project Title:Atypical Molecular Basis for Drug Resistance to Mitochondrial Function Inhibitors in AQ: A Plasmodium falciparum
Project Summary:In this study, we present a clear genotype for the P. falciparum SB1-A6 acridone-resistant clonal parasite strain and, through a combination of targeted and whole-cell methods, establish that the mechanism of resistance to both cytochrome bc1 and DHODH inhibitors results from the contribution of multiple genetic polymorphisms. We find that P. falciparum SB1-A6 accumulates both a copy number variation and a specific mutation in PfDHODH, and both of these genetic polymorphisms contribute to the panresistant phenotype. This study uncovers a mechanism of cross-resistance between PfDHODH and mtETC inhibitors and serves as a cautionary note to future antimalarial combination therapy formulations containing such drugs.
Institute:U.S. Food & Drug Administration
Last Name:Painter
First Name:Heather
Address:10903 New Hampshire Ave., WO 52/72-5324, Silver Spring, MD 20993
Email:Heather.Painter@fda.hhs.gov
Phone:240-402-2040

Subject:

Subject ID:SU001729
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 Genotype Treatment
SA1517319_A6_AT1Drug Resistant Atovaquone
SA15173219_A6_AT2Drug Resistant Atovaquone
SA15173328_A6_AT3Drug Resistant Atovaquone
SA15173431_A6_CT3Drug Resistant Control
SA15173521_A6_CT2Drug Resistant Control
SA1517367_A6_CT1Drug Resistant Control
SA1517378_A6_DT1Drug Resistant DSM-1
SA15173820_A6_DT2Drug Resistant DSM-1
SA15173926_A6_DT3Drug Resistant DSM-1
SA15174017_D6_DT2Drug Resistant DSM-1
SA15174112_D6_AT1Wild-type Atovaquone
SA15174216_D6_AT2Wild-type Atovaquone
SA15174325_D6_AT3Wild-type Atovaquone
SA15174410_D6_CT1Wild-type Control
SA15174529_D6_CT3Wild-type Control
SA15174618_D6_CT2Wild-type Control
SA15174711_D6_DT1Wild-type DSM-1
Showing results 1 to 17 of 17

Collection:

Collection ID:CO001722
Collection Summary:Cells were pelleted and the media aspirated prior to methanol extraction
Sample Type:Plasmodium cells

Treatment:

Treatment ID:TR001742
Treatment Summary:Trophozoite-stage Plasmodium infected RBCs were treated with 10x IC50 of either drug for 2.5 hours

Sample Preparation:

Sampleprep ID:SP001735
Sampleprep Summary:90% Methanol/10% water at 50:1 solvent/cell pellet followed by vortexing and clarification via centrifugation
Processing Method:Lysis
Processing Storage Conditions:4℃
Extract Cleanup:Clarification via centrifugation followed by nitrogen drying
Extract Storage:-80℃
Sample Resuspension:6X pellet volume of HPLC H2O
Sample Spiking:Internal Standard 13C4, 15N1-Aspartate used for sample preparation normalizer

Combined analysis:

Analysis ID AN002699
Analysis type MS
Chromatography type Reversed phase
Chromatography system Thermo Exactive Orbitrap Plus
Column Phenomenex Synergi Hydro RP (100 x 2mm,2.5um)
MS Type ESI
MS instrument type Orbitrap
MS instrument name Thermo Q Exactive Orbitrap
Ion Mode NEGATIVE
Units intensity

Chromatography:

Chromatography ID:CH001991
Chromatography Summary:Low pH polar
Instrument Name:Thermo Exactive Orbitrap Plus
Column Name:Phenomenex Synergi Hydro RP (100 x 2mm,2.5um)
Chromatography Type:Reversed phase

MS:

MS ID:MS002497
Analysis ID:AN002699
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Proprietary analytical software for integration and peak picking
Ion Mode:NEGATIVE
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