| Literature DB >> 23043329 |
Gabriel Martínez-Botella1, 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.
Abstract
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 μg/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.Entities:
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Year: 2012 PMID： 23043329 DOI： 10.1021/jm3011806
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446