학술논문
Discovery of Selectiveand Potent Inhibitors of Gram-PositiveBacterial Thymidylate Kinase (TMK).
Document Type
Article
Author
Martínez-Botella, Gabriel; Breen, John N.; Duffy, James E. S.; Dumas, Jacques; Geng, Bolin; Gowers, Ian K.; Green, OluyinkaM.; 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, JosephV.; Olivier, Nelson B.; Otterson, Linda G.
Source
Subject
*KINASE inhibitors
*GRAM-positive bacterial infections
*BACTERIAL DNA
*X-ray crystallography
*DRUG development
*METHICILLIN-resistant staphylococcus aureus
*DIASTEREOISOMERS
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Language
ISSN
0022-2623
Abstract
Thymidylate kinase (TMK) is an essential enzyme in bacterialDNAsynthesis. The deoxythymidine monophosphate (dTMP) substrate bindingpocket 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 pneumoniaeand Staphylococcus aureusTMK. MICs < 1 μg/mLwere achieved against methicillin-resistant S. aureus(MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus(VRE). Log Dadjustments yieldedsingle diastereomers 14(TK-666) and 46,showing a broad antibacterial spectrum against Gram-positive bacteriaand excellent selectivity against the human thymidylate kinase ortholog. [ABSTRACT FROM AUTHOR]