Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus
Abstract
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.
- Authors:
-
- Stony Brook Univ., NY (United States). Inst. of Chemical Biology & Drug Discovery
- Brookhaven National Lab. (BNL), Upton, NY (United States). Biosciences Dept.
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1160044
- Report Number(s):
- BNL-106134-2014-JA
Journal ID: ISSN 0223-5234; R&D Project: MO-085; KP1602010
- Grant/Contract Number:
- AC02-98CH10886; GM102864
- Resource Type:
- Accepted Manuscript
- Journal Name:
- European Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 88; Journal Issue: C; Journal ID: ISSN 0223-5234
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 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
Citation Formats
Wang, Hui, Lu, Yang, Liu, Li, Kim, Sung Won, Hooker, Jacob M., Fowler, Joanna S., and Tonge, Peter J. Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus. United States: N. p., 2014.
Web. doi:10.1016/j.ejmech.2014.09.008.
Wang, Hui, Lu, Yang, Liu, Li, Kim, Sung Won, Hooker, Jacob M., Fowler, Joanna S., & Tonge, Peter J. Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus. United States. https://doi.org/10.1016/j.ejmech.2014.09.008
Wang, Hui, Lu, Yang, Liu, Li, Kim, Sung Won, Hooker, Jacob M., Fowler, Joanna S., and Tonge, Peter J. Sat .
"Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus". United States. https://doi.org/10.1016/j.ejmech.2014.09.008. https://www.osti.gov/servlets/purl/1160044.
@article{osti_1160044,
title = {Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus},
author = {Wang, Hui and Lu, Yang and Liu, Li and Kim, Sung Won and Hooker, Jacob M. and Fowler, Joanna S. and Tonge, Peter J.},
abstractNote = {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.},
doi = {10.1016/j.ejmech.2014.09.008},
journal = {European Journal of Medicinal Chemistry},
number = C,
volume = 88,
place = {United States},
year = {Sat Sep 06 00:00:00 EDT 2014},
month = {Sat Sep 06 00:00:00 EDT 2014}
}
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Works referencing / citing this record:
BindingDB Entry 50044693: Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus.
dataset, January 2016
- None, None
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