Towards Gram-negative antivirulence drugs: new inhibitors of HldE kinase.
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.
Desroy
Nicolas
N
MUTABILIS SA, 102 Avenue Gaston Roussel, 93230 Romainville, France. nicolas.desroy@mutabilis.fr
Moreau
François
F
Briet
Sophia
S
Le Fralliec
Géraldine
G
Floquet
Stephanie
S
Durant
Lionel
L
Vongsouthi
Vanida
V
Gerusz
Vincent
V
Denis
Alexis
A
Escaich
Sonia
S
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology; D006539:Heptoses / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D006539:Heptoses; D009097:Multienzyme Complexes; D017853:Phosphotransferases (Alcohol Group Acceptor); C022534:ribokinase; D009713:Nucleotidyltransferases; C445302:D,D heptose 7-phosphate kinase-D,D-heptose 1-phosphate adenylyltransferase, E coli