title: Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae.
abstract: Survival of the human pathogen Streptococcus pneumoniae requires a functional mevalonate pathway, which produces isopentenyl diphosphate, the essential building block of isoprenoids. Flux through this pathway appears to be regulated at the mevalonate kinase (MK) step, which is strongly feedback-inhibited by diphosphomevalonate (DPM), the penultimate compound in the pathway. The human mevalonate pathway is not regulated by DPM, making the bacterial pathway an attractive antibiotic target. Since DPM has poor drug characteristics, being highly charged, we propose to use unphosphorylated, cell-permeable prodrugs based on mevalonate that will be phosphorylated in turn by MK and phosphomevalonate kinase (PMK) to generate the active compound in situ. To test the limits of this approach, we synthesized a series of C(3)-substituted mevalonate analogues to probe the steric and electronic requirements of the MK and PMK active sites. MK and PMK accepted substrates with up to two additional carbons, showing a preference for small substituents. This result establishes the feasibility of using a prodrug strategy for DPM-based antibiotics in S. pneumoniae and identified several analogues to be tested as inhibitors of MK. Among the substrates accepted by both enzymes were cyclopropyl, vinyl, and ethynyl mevalonate analogues that, when diphosphorylated, might be mechanism-based inactivators of the next enzyme in the pathway, diphosphomevalonate decarboxylase.
authors.affiliation: Department of Chemistry, Center for Molecular Innovation and Drug Discovery, and Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208-3113, United States.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudoh
authors.forename: Chan Sun
authors.initials: CS
authors.lastname: Park
authors.forename: Scott T
authors.initials: ST
authors.lastname: Lefurgy
authors.forename: Meihao
authors.initials: M
authors.lastname: Sun
authors.forename: Theodore
authors.initials: T
authors.lastname: Michels
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Leyh
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D015195:Drug Design; D006801:Humans; D008798:Mevalonic Acid / Q000031:analogs & derivatives* / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000201:enzymology*; D013729:Terpenes / Q000378:metabolism
chemical_list: D011355:Prodrugs; D013729:Terpenes; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D017856:Phosphotransferases (Phosphate Group Acceptor); C022371:phosphomevalonate kinase; D008798:Mevalonic Acid