Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)

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• 作者：Gabriel Mart铆nez-Botella ; John N. Breen ; James E. S. Duffy ; Jacques Dumas ; Bolin Geng ; Ian K. Gowers ; Oluyinka M. Green ; Satenig Guler ; Martin F. Hentemann ; Felix A. Hernandez-Juan ; Diane Joseph-McCarthy ; Sameer Kawatkar ; Nicholas A. Larsen ; Ovadia Lazari ; James T. Loch ; Jacqueline A. Macritchie ; Andrew R. McKenzie ; Joseph V. Newman ; Nelson B. Olivier ; Linda G. Otterson ; Andrew P. Owens ; Jon Read ; David W. Sheppard ; Thomas A. Keating
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10010-10021
• 全文大小：553K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 渭g/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.