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

Journal Article · · European Journal of Medicinal Chemistry
 [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.
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Here we evaluated 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 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.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-98CH10886; GM102864
OSTI ID:
1160044
Report Number(s):
BNL-106134-2014-JA; R&D Project: MO-085; KP1602010
Journal Information:
European Journal of Medicinal Chemistry, Vol. 88, Issue C; ISSN 0223-5234
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 7 works
Citation information provided by
Web of Science

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Cited By (1)

BindingDB Entry 50044693: Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus. dataset January 2016

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Related Subjects

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