Abstract
Gram-negative bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochemical assay suitable for high-throughput screening allowed the discovery of inhibitors 1 and 2 of HldE kinase. Study of the structure-activity relationship of this series of inhibitors led to highly potent compounds.
MeSH terms
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Amino Acid Sequence
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / pharmacology*
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Escherichia coli / drug effects
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Escherichia coli / enzymology
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Gram-Negative Bacteria / drug effects*
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Gram-Negative Bacteria / enzymology
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Heptoses / metabolism
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Humans
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Inhibitory Concentration 50
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Kinetics
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Molecular Sequence Data
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Multienzyme Complexes / antagonists & inhibitors*
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Nucleotidyltransferases / antagonists & inhibitors*
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
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Sequence Alignment
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Sequence Homology, Amino Acid
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Heptoses
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Multienzyme Complexes
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Phosphotransferases (Alcohol Group Acceptor)
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ribokinase
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Nucleotidyltransferases
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D,D heptose 7-phosphate kinase-D,D-heptose 1-phosphate adenylyltransferase, E coli