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

Here we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a K i value of 0.01 nM and a residence time of 750 min on the enzyme target 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.
 [1] ;  [1] ;  [1] ;  [2] ;  [2] ;  [2] ;  [1]
  1. Stony Brook Univ., NY (United States). Inst. of Chemical Biology & Drug Discovery
  2. Brookhaven National Lab. (BNL), Upton, NY (United States). Biosciences Dept.
Publication Date:
Report Number(s):
Journal ID: ISSN 0223-5234; R&D Project: MO-085; KP1602010
Grant/Contract Number:
AC02-98CH10886; GM102864
Accepted Manuscript
Journal Name:
European Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 88; Journal Issue: C; Journal ID: ISSN 0223-5234
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; Staphylococcus aureus; staph aureus enoyl-ACP reductase (saFabI); pharmacokinetics; pharmacodynamics; PET (positron emission tomography); antibacterial efficacy; positron emission tomography (PET) facility
OSTI Identifier: