title: Enediol mimics as inhibitors of the D-arabinose 5-phosphate isomerase (KdsD) from Francisella tularensis.
abstract: We explored the D-arabinose 5-phosphate isomerase (KdsD, E.C. 5.3.1.13) from Francisella tularensis, a highly infectious gram-negative pathogen that has raised concern as a potential bioweapon, as a target for the development of novel chemotherapeutics. F. tularensis KdsD was expressed in Escherichia coli from a synthetic gene, purified, and characterized. A group of hydroxamates designed to be mimics of the putative enediol intermediate in the enzyme's catalytic mechanism were prepared and tested as inhibitors of F. tularensis KdsD. The best inhibitor, which has an IC(50) of 7 μM, is the most potent KdsD inhibitor reported to date.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA. ayep@umich.edu
authors.forename: Alejandra
authors.initials: A
authors.lastname: Yep
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Sorenson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wilson
authors.forename: H D Hollis
authors.initials: HD
authors.lastname: Showalter
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Keller
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Woodard
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D005604:Francisella tularensis / Q000187:drug effects* / Q000201:enzymology; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure
chemical_list: D000438:Alcohols; D000475:Alkenes; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D019747:Aldose-Ketose Isomerases; C041486:arabinose-5-phosphate isomerase