Structural-Functional Studies of Burkholderia cenocepacia D-Glycero-beta-D-manno-heptose 7-Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence Properties

Ting-Wai Lee, Theodore B. Verhey, Pavel A. Antiperovitch, Dmytro Atamanyuk, Nicolas Desroy, Chrystelle Oliveira, Alexis Denis, Vincent Gerusz, Elodie Drocourt, Slade A. Loutet, Mohamad A. Hamad, Christian Stanetty, Sara N. Andres, Seiji Sugiman-Marangos, Paul Kosma, Miguel A. Valvano, Francois Moreau, Murray S. Junop*

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of D-glycero-beta-D-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.

Original languageEnglish
Pages (from-to)1405-1417
JournalJournal of Medicinal Chemistry
Volume56
Issue number4
Early online date20 Dec 2012
DOIs
Publication statusPublished - 28 Feb 2013

Keywords

  • ESCHERICHIA-COLI
  • BACTERIA
  • CELL-SURFACE
  • OUTER-MEMBRANE PERMEABILITY
  • RIBOKINASE
  • MOLECULAR-BASIS
  • LIPOPOLYSACCHARIDE BIOSYNTHESIS
  • DRUG DISCOVERY
  • PHOSPHATASE GMHB
  • SEDOHEPTULOSE-7-PHOSPHATE ISOMERASE

Cite this

Lee, T-W., Verhey, T. B., Antiperovitch, P. A., Atamanyuk, D., Desroy, N., Oliveira, C., Denis, A., Gerusz, V., Drocourt, E., Loutet, S. A., Hamad, M. A., Stanetty, C., Andres, S. N., Sugiman-Marangos, S., Kosma, P., Valvano, M. A., Moreau, F., & Junop, M. S. (2013). Structural-Functional Studies of Burkholderia cenocepacia D-Glycero-beta-D-manno-heptose 7-Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence Properties. Journal of Medicinal Chemistry, 56(4), 1405-1417. https://doi.org/10.1021/jm301483h