title: Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD.
abstract: The methylerythritol phosphate (MEP) pathway is an essential metabolic pathway found in malaria parasites, but absent in mammals, making it a highly attractive target for the discovery of novel and selective antimalarial therapies. Using high-throughput screening, we have identified 2-phenyl benzo[d]isothiazol-3(2H)-ones as species-selective inhibitors of Plasmodium spp. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD), the third catalytic enzyme of the MEP pathway. 2-Phenyl benzo[d]isothiazol-3(2H)-ones display nanomolar inhibitory activity against P. falciparum and P. vivax IspD and prevent the growth of P. falciparum in culture, with EC50values below 400 nM. In silico modeling, along with enzymatic, genetic and crystallographic studies, have established a mechanism-of-action involving initial non-covalent recognition of inhibitors at the IspD binding site, followed by disulfide bond formation through attack of an active site cysteine residue on the benzo[d]isothiazol-3(2H)-one core. The species-selective inhibitory activity of these small molecules against Plasmodium spp. IspD and cultured parasites suggests they have potential as lead compounds in the pursuit of novel drugs to treat malaria.
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Price
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Armstrong
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Leah S
authors.initials: LS
authors.lastname: Imlay
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Hodge
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: C
authors.initials: C
authors.lastname: Pidathala
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Roberts
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jooyoung
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marwa
authors.initials: M
authors.lastname: Mikati
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Lawrenson
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Niraj H
authors.initials: NH
authors.lastname: Tolia
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Audrey R Odom
authors.initials: AR
authors.lastname: John
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D019916:Choline-Phosphate Cytidylyltransferase / Q000737:chemistry*; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004896:Erythritol / Q000031:analogs & derivatives / Q000737:chemistry; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000517:prevention & control*; D010963:Plasmodium falciparum / Q000187:drug effects*; D010966:Plasmodium vivax / Q000187:drug effects*; D011994:Recombinant Proteins / Q000737:chemistry; D013403:Sugar Phosphates / Q000737:chemistry
chemical_list: C114232:2-C-methylerythritol 4-phosphate; D000962:Antimalarials; D052160:Benzothiazoles; D011994:Recombinant Proteins; D013403:Sugar Phosphates; D019916:Choline-Phosphate Cytidylyltransferase; D004896:Erythritol