title: Novel HldE-K inhibitors leading to attenuated Gram negative bacterial virulence.
abstract: We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 μg/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors.
authors: Medicinal Chemistry, Mutabilis, 102 Avenue Gaston Roussel, 93230 Romainville, France.
authors: Nicolas
authors: N
authors: Desroy
authors: Alexis
authors: A
authors: Denis
authors: Chrystelle
authors: C
authors: Oliveira
authors: Dmytro
authors: D
authors: Atamanyuk
authors: Sophia
authors: S
authors: Briet
authors: Fabien
authors: F
authors: Faivre
authors: Géraldine
authors: G
authors: LeFralliec
authors: Yannick
authors: Y
authors: Bonvin
authors: Mayalen
authors: M
authors: Oxoby
authors: Sonia
authors: S
authors: Escaich
authors: Stéphanie
authors: S
authors: Floquet
authors: Elodie
authors: E
authors: Drocourt
authors: Vanida
authors: V
authors: Vongsouthi
authors: Lionel
authors: L
authors: Durant
authors: François
authors: F
authors: Moreau
authors: Theodore B
authors: TB
authors: Verhey
authors: Ting-Wai
authors: TW
authors: Lee
authors: Murray S
authors: MS
authors: Junop
authors: Vincent
authors: V
authors: Gerusz
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects* / Q000472:pathogenicity; D008070:Lipopolysaccharides / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D052160:Benzothiazoles; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D014227:Triazines; D017853:Phosphotransferases (Alcohol Group Acceptor); D009713:Nucleotidyltransferases; C445302:D,D heptose 7-phosphate kinase-D,D-heptose 1-phosphate adenylyltransferase, E coli