title: Development of inhibitors of the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway enzymes as potential anti-infective agents.
abstract: Important pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum, the causative agents of tuberculosis and malaria, respectively, and plants, utilize the 2C-methyl-D-erythritol 4-phosphate (MEP, 5) pathway for the biosynthesis of isopentenyl diphosphate (1) and dimethylallyl diphosphate (2), the universal precursors of isoprenoids, while humans exclusively utilize the alternative mevalonate pathway for the synthesis of 1 and 2. This distinct distribution, together with the fact that the MEP pathway is essential in numerous organisms, makes the enzymes of the MEP pathway attractive drug targets for the development of anti-infective agents and herbicides. Herein, we review the inhibitors reported over the past 2 years, in the context of the most important older developments and with a particular focus on the results obtained against enzymes of pathogenic organisms. We will also discuss new discoveries in terms of structural and mechanistic features, which can help to guide a rational development of inhibitors.
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen , Nijenborgh 7, NL-9747 AG Groningen, The Netherlands.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Masini
authors.forename: Anna K H
authors.initials: AK
authors.lastname: Hirsch
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004896:Erythritol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D019761:Phosphorus-Oxygen Lyases / Q000037:antagonists & inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D013403:Sugar Phosphates / Q000037:antagonists & inhibitors*
chemical_list: C114232:2-C-methylerythritol 4-phosphate; D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D009097:Multienzyme Complexes; D013403:Sugar Phosphates; D010088:Oxidoreductases; C109866:ispH protein, E coli; C522017:IspD protein, E coli; D017853:Phosphotransferases (Alcohol Group Acceptor); C404502:IspE protein, E coli; D019761:Phosphorus-Oxygen Lyases; C400181:ISPF protein, E coli; D019747:Aldose-Ketose Isomerases; D004896:Erythritol