Binding Inhibitors of the Bacterial Sliding Clamp by Design Academic Article uri icon

abstract

  • The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β(2) sliding clamp is an essential component of the replicative machinery, providing a platform for recruitment and function of other replisomal components and ensuring polymerase processivity during DNA replication and repair. A single binding region of the clamp is utilized by its binding partners, which all contain conserved binding motifs. The C-terminal Leu and Phe residues of these motifs are integral to the binding interaction. We acquired three-dimensional structural information on the binding site in β(2) by a study of the binding of modified peptides. Development of a three-dimensional pharmacophore based on the C-terminal dipeptide of the motif enabled identification of compounds that on further development inhibited α-β(2) interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β(2), as a starting point for further inhibitor design.

authors

  • Wijffels, G
  • Johnson, WM
  • Oakley, AJ
  • Turner, K
  • Epa, VC
  • Briscoe, SJ
  • Polley, M
  • Liepa, AJ
  • Hofmann, A
  • Buchardt, J
  • Christensen, C
  • Prosselkov, P
  • Dalrymple, BP
  • Alewood, PF
  • Jennings, PA
  • Dixon, NE
  • Winkler, DA

publication date

  • 2011