Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus

Eur J Med Chem. 2014 Dec 17:88:66-73. doi: 10.1016/j.ejmech.2014.09.008. Epub 2014 Sep 6.

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.

Keywords: Antibacterial efficacy; Pharmacodynamics; Pharmacokinetics; Positron emission tomography; Staph aureus enoyl-ACP reductase (saFabI).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / analysis
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / pharmacology
  • Carbon Isotopes
  • Case-Control Studies
  • Dose-Response Relationship, Drug
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*
  • Enzyme Inhibitors / analysis
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / pharmacology
  • Male
  • Mice
  • Molecular Structure
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / microbiology*
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / enzymology*
  • Tissue Distribution

Substances

  • Anti-Bacterial Agents
  • Carbon Isotopes
  • Enzyme Inhibitors
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)