| Autor: |
Imlay LS; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Armstrong CM; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Masters MC; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Li T; College of Medicine, University of Toledo, Toledo, Ohio 43614, United States., Price KE; Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K., Edwards RL; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Mann KM; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Li LX; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Stallings CL; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Berry NG; Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K., O'Neill PM; Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K., Odom AR; 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. |
| Abstrakt: |
As resistance to current therapies spreads, novel antimalarials are urgently needed. In this work, we examine the potential for therapeutic intervention via the targeting of Plasmodium IspD (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, inhibits Plasmodium falciparum growth, 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 the Pf ISPD genetic 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. |
