In Vivo Validation of Thymidylate Kinase (TMK) with a Rationally Designed, Selective Antibacterial Compound
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- 作者：Thomas A. Keating ; Joseph V. Newman ; Nelson B. Olivier ; Linda G. Otterson ; Beth Andrews ; P. Ann Boriack-Sjodin ; John N. Breen ; Peter Doig ; Jacques Dumas ; Eric Gangl ; Oluyinka M. Green ; Satenig Y. Guler ; Martin F. Hentemann ; Diane Joseph-McCarthy ; Sameer Kawatkar ; Amy Kutschke ; James T. Loch ; Andrew R. McKenzie ; Selvi Pradeepan ; Swati Prasad ; Gabriel Mart铆nez-Botella
- 刊名：ACS Chemical Biology
- 出版年：2012
- 出版时间：November 16, 2012
- 年：2012
- 卷：7
- 期：11
- 页码：1866-1872
- 全文大小：366K
- 年卷期：v.7,no.11(November 16, 2012)
- ISSN：1554-8937
文摘
There is an urgent need for new antibacterials that pinpoint novel targets and thereby avoid existing resistance mechanisms. We have created novel synthetic antibacterials through structure-based drug design that specifically target bacterial thymidylate kinase (TMK), a nucleotide kinase essential in the DNA synthesis pathway. A high-resolution structure shows compound TK-666 binding partly in the thymidine monophosphate substrate site, but also forming new induced-fit interactions that give picomolar affinity. TK-666 has potent, broad-spectrum Gram-positive microbiological activity (including activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus), bactericidal action with rapid killing kinetics, excellent target selectivity over the human ortholog, and low resistance rates. We demonstrate in vivo efficacy against S. aureus in a murine infected-thigh model. This work presents the first validation of TMK as a compelling antibacterial target and provides a rationale for pursuing novel clinical candidates for treating Gram-positive infections through TMK.