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.
MeSH terms
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / pharmacology*
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Benzoates / chemical synthesis
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Benzoates / pharmacology*
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Catalytic Domain
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Crystallography, X-Ray
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Enterococcus / drug effects*
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Humans
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Methicillin-Resistant Staphylococcus aureus / drug effects*
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Structure
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Nucleoside-Phosphate Kinase / antagonists & inhibitors*
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Nucleoside-Phosphate Kinase / metabolism
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Staphylococcus aureus / drug effects*
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Streptococcus pneumoniae / drug effects*
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Structure-Activity Relationship
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Thymine / analogs & derivatives*
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Thymine / chemical synthesis
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Thymine / pharmacology
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Vancomycin Resistance / drug effects*
Substances
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2-(3-bromophenoxy)-4-(1-(3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl)hexyl)benzoic acid
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2-(3-bromophenoxy)-4-(3,3-dimethyl-1-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1-(2H)-yl)piperidin-1-yl)butyl)benzoic acid
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Anti-Bacterial Agents
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Benzoates
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Nucleoside-Phosphate Kinase
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dTMP kinase
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Thymine