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

European Journal of Medicinal Chemistry
Hui WangPeter J Tonge

Abstract

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.

References

Jan 1, 1988·Therapeutic Drug Monitoring·J BarreJ P Tillement
Jan 9, 1998·Drug Metabolism Reviews·A J FischmanR H Rubin
May 8, 1999·Science·C Walsh
Dec 1, 2001·Trends in Microbiology·S J PeacockF D Lowy
Sep 18, 2002·Antimicrobial Agents and Chemotherapy·David J PayneWilliam F Huffman
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Richa RawatPeter J Tonge
Apr 24, 2004·Antimicrobial Agents and Chemotherapy·Markus MüllerHartmut Derendorf
Jul 23, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Li-Quan WangMargaret O James
Dec 8, 2004·Current Drug Metabolism·Oliver Langer, Markus Müller
Dec 17, 2004·Journal of Veterinary Pharmacology and Therapeutics·Q A McKellarD G Jones
Sep 6, 2006·Journal of Toxicology and Environmental Health. Part a·Gunilla Sandborgh-EnglundJan Ekstrand
Jul 4, 2007·The Journal of Antimicrobial Chemotherapy·Hee Soo ParkJin-Hwan Kwak
Feb 9, 2008·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Dawn M SievertJeffrey C Hageman
May 7, 2008·Bioorganic & Medicinal Chemistry Letters·Christopher W am EndePeter J Tonge
Sep 8, 2009·The Journal of Antimicrobial Chemotherapy·Kathleen EnglandRichard A Slayden
Oct 14, 2009·Antimicrobial Agents and Chemotherapy·Christian QueckenbergUwe Fuhr
Aug 10, 2011·Antimicrobial Agents and Chemotherapy·S EscaichC Soulama-Mouze
Aug 13, 2011·Annals of Nuclear Medicine·Alberto Signore, Andor W J M Glaudemans
Apr 3, 2012·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Jotam G PasipanodyaTawanda Gumbo
Mar 20, 2013·Nature Chemical Biology·Gabriel M SimonBenjamin F Cravatt

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Citations

May 20, 2015·Applied Radiation and Isotopes : Including Data, Instrumentation and Methods for Use in Agriculture, Industry and Medicine·Colleen SheaWenchao Qu
Oct 14, 2014·European Journal of Medicinal Chemistry·Lyn H Jones, Christian Heinis

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