title: Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus.
abstract: The pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a Ki value of 0.01 nM and a residence time of 750 min on the enzyme target, has been evaluated in mice. PT119 was found to have promising antibacterial activity in two different S. aureus infection models: it caused a 3 log reduction in the CFU's in a mouse thigh muscle infection model and increased the survival rate from 0% to 50% in a mouse systemic infection model. PT119 was then radiolabeled with carbon-11 to evaluate its biodistribution and PK in both healthy and S. aureus infected mice using positron emission tomography (PET). The biodistribution of [11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ∼1 h of analysis permitted by the carbon-11 half life. This approach provides important data for PK/PD modeling and is the first step in identifying radiotracers that can non-invasively image bacterial infection in vivo.
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: peter.tonge@stonybrook.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000032:analysis / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D002247:Carbon Isotopes; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000032:analysis / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D002247:Carbon Isotopes; D004791:Enzyme Inhibitors; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Antibacterial efficacy; Pharmacodynamics; Pharmacokinetics; Positron emission tomography; Staph aureus enoyl-ACP reductase (saFabI)