European Journal of Medicinal Chemistry 2014-12-17

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

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

文献索引：Eur. J. Med. Chem. 88 , 66-73, (2014)

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摘要

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.Copyright © 2014 Elsevier Masson SAS. All rights reserved.