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

作者：Martinez Botella Gabriel^*; Breen John N; Duffy James E S; Dumas Jacques; Geng Bolin; Gowers Ian K; Green Oluyinka M; Guler Satenig; Hentemann Martin F; Hernandez Juan Felix A; Joseph McCarthy Diane; Kawatkar Sameer; Larsen Nicholas A; Lazari Ovadia; Loch James T; Macritchie Jacqueline A; McKenzie Andrew R; Newman Joseph V; Olivier Nelson B; Otterson Linda G; Owens Andrew P; Read Jon; Sheppard David W; Keating Thomas A

来源：Journal of Medicinal Chemistry, 2012, 55(22): 10010-10021.

DOI：10.1021/jm3011806

Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in 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 mu 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.

• 出版日期2012-11-22