title: PlasmodiumIspD (2-C-Methyl-D-erythritol 4-Phosphate Cytidyltransferase), an Essential and Druggable Antimalarial Target.
abstract: As resistance to current therapies spreads, novel antimalarials are urgently needed. In this work, we examine the potential for therapeutic intervention via the targeting ofPlasmodiumIspD (2-C-methyl-D-erythritol 4-phosphate cytidyltransferase), the second dedicated enzyme of the essential methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis. Enzymes of this pathway represent promising therapeutic targets because the pathway is not present in humans. The Malaria Box compound, MMV008138, inhibitsPlasmodium falciparumgrowth, and PfIspD has been proposed as a candidate intracellular target. We find that PfIspD is the sole intracellular target of MMV008138 and characterize the mode of inhibition and target-based resistance, providing chemical validation of this target. Additionally, we find that thePf ISPDgenetic locus is refractory to disruption in malaria parasites, providing independent genetic validation for efforts targeting this enzyme. This work provides compelling support for IspD as a druggable target for the development of additional, much-needed antimalarial agents.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Leah S
authors.initials: LS
authors.lastname: Imlay
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Armstrong
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Mary Clare
authors.initials: MC
authors.lastname: Masters
authors.affiliation: College of Medicine, University of Toledo, Toledo, Ohio 43614, United States.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Price
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Edwards
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Mann
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Lucy X
authors.initials: LX
authors.lastname: Li
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Stallings
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Audrey R
authors.initials: AR
authors.lastname: Odom
keywords: IspD; MEP pathway; MMV008138; homology model; malaria; plasmodium