title: Slow-onset inhibition of the FabI enoyl reductase from francisella tularensis: residence time and in vivo activity.
abstract: Francisella tularensis is a highly virulent and contagious Gram-negative intracellular bacterium that causes the disease tularemia in mammals. The high infectivity and the ability of the bacterium to survive for weeks in a cool, moist environment have raised the possibility that this organism could be exploited deliberately as a potential biological weapon. Fatty acid biosynthesis (FAS-II) is essential for bacterial viability and has been validated as a target for the discovery of novel antibacterials. The FAS-II enoyl reductase ftuFabI has been cloned and expressed, and a series of diphenyl ethers have been identified that are subnanomolar inhibitors of the enzyme with MIC90 values as low as 0.00018 microg mL(-1). The existence of a linear correlation between the Ki and MIC values strongly suggests that the antibacterial activity of the diphenyl ethers results from direct inhibition of ftuFabI within the cell. The compounds are slow-onset inhibitors of ftuFabI, and the residence time of the inhibitors on the enzyme correlates with their in vivo activity in a mouse model of tularemia infection. Significantly, the rate of breakdown of the enzyme-inhibitor complex is a better predictor of in vivo activity than the overall thermodynamic stability of the complex, a concept that has important implications for the discovery of novel chemotherapeutics that normally rely on equilibrium measurements of potency.
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York11794-3400, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Lu
authors.forename: Kathleen
authors.initials: K
authors.lastname: England
authors.forename: Christopher
authors.initials: C
authors.lastname: am Ende
authors.forename: James J
authors.initials: JJ
authors.lastname: Truglio
authors.forename: Sylvia
authors.initials: S
authors.lastname: Luckner
authors.forename: B Gopal
authors.initials: BG
authors.lastname: Reddy
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Marlenee
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Knudson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bowen
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D054872:Fatty Acid Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005604:Francisella tularensis / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008813:Mice, Inbred ICR; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014406:Tularemia / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D054872:Fatty Acid Synthesis Inhibitors; D010647:Phenyl Ethers; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D054889:Fatty Acid Synthase, Type II