title: Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action.
abstract: High-throughput phenotypic screening of chemical libraries has resulted in the identification of thousands of compounds with potent antimalarial activity, although in most cases, the mechanism(s) of action of these compounds remains unknown. Here we have investigated the mode of action of 90 antimalarial compounds derived from the Malaria Box collection using high-coverage, untargeted metabolomics analysis. Approximately half of the tested compounds induced significant metabolic perturbations in in vitro cultures of Plasmodium falciparum In most cases, the metabolic profiles were highly correlated with known antimalarials, in particular artemisinin, the 4-aminoquinolines, or atovaquone. Select Malaria Box compounds also induced changes in intermediates in essential metabolic pathways, such as isoprenoid biosynthesis (i.e., 2-C-methyl-d-erythritol 2,4-cyclodiphosphate) and linolenic acid metabolism (i.e., traumatic acid). This study provides a comprehensive database of the metabolic perturbations induced by chemically diverse inhibitors and highlights the utility of metabolomics for triaging new lead compounds and defining specific modes of action, which will assist with the development and optimization of new antimalarial drugs.
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia darren.creek@monash.edu malcolmm@unimelb.edu.au.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
authors: Darren J
authors: 0000-0001-7497-7082
authors: DJ
authors: Creek
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
authors: Hwa H
authors: HH
authors: Chua
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
authors: Simon A
authors: SA
authors: Cobbold
authors: Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
authors: Brunda
authors: B
authors: Nijagal
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
authors: James I
authors: JI
authors: MacRae
authors: Burnet Institute, Melbourne, Australia.
authors: Benjamin K
authors: BK
authors: Dickerman
authors: Burnet Institute, Melbourne, Australia.|Monash University, Melbourne, Australia.
authors: Paul R
authors: PR
authors: Gilson
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
authors: Stuart A
authors: SA
authors: Ralph
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.|Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
authors: Malcolm J
authors: MJ
authors: McConville
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D053626:Atovaquone / Q000494:pharmacology; D002478:Cells, Cultured; D002853:Chromatography, Liquid / Q000379:methods; D016000:Cluster Analysis; D062126:Databases, Chemical; D003998:Dicarboxylic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D058990:Molecular Targeted Therapy / Q000379:methods*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013729:Terpenes / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D037621:Artemisinins; D003998:Dicarboxylic Acids; D054852:Small Molecule Libraries; D013729:Terpenes; C031327:artemisinin; C509089:traumatic acid; D053626:Atovaquone