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

Wang, Hui; Lu, Yang; Liu, Li; Kim, Sung Won; Hooker, Jacob M.; Fowler, Joanna S.; Tonge, Peter J.

doi:10.1016/j.ejmech.2014.09.008

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

Journal Article · Sat Sep 06 00:00:00 EDT 2014 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2014.09.008· OSTI ID:1160044

Wang, Hui ^[1]; Lu, Yang ^[1]; Liu, Li ^[1]; Kim, Sung Won ^[2]; Hooker, Jacob M. ^[2]; Fowler, Joanna S. ^[2]; Tonge, Peter J. ^[1]

Stony Brook Univ., NY (United States). Inst. of Chemical Biology & Drug Discovery
Brookhaven National Lab. (BNL), Upton, NY (United States). Biosciences Dept.

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.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)

Grant/Contract Number:: AC02-98CH10886

OSTI ID:: 1160044

Report Number(s):: BNL--106134-2014-JA; KP1602010

Journal Information:: European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Journal Issue: C Vol. 88; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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BindingDB Entry 50044693: Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus. No authors listed BindingDB https://doi.org/10.7270/q25t3n3s	dataset	January 2016

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

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