Phosphinate inhibitors of UDP-N-acetylmuramoyl-L-alanyl-D-glutamate: L-lysine ligase (MurE)

Arch Pharm (Weinheim). 2007 Mar;340(3):127-34. doi: 10.1002/ardp.200600191.

Abstract

The increasing emergence of pathogenic bacterial strains with high resistance to antibiotic therapy has created an urgent need for the development of new antibacterial agents that are directed towards novel targets. We have focused our attention on the Mur ligases (MurC-F), which catalyze the early steps of bacterial peptidoglycan biosynthesis, and which to date represent under-exploited targets for antibacterial drug design. We show that some of our phosphinate inhibitors of UDP-N-acetylmuramoyl-L-alanyl:D-glutamate ligase (MurD) also inhibits UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:L-lysine ligase (MurE). To obtain new information on their structure-activity relationships, three new, structurally related phosphinates were synthesized and evaluated for inhibition of MurD and MurE.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Computer Simulation
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Peptide Synthases / antagonists & inhibitors
  • Peptide Synthases / chemistry*
  • Peptide Synthases / isolation & purification
  • Phosphinic Acids / chemical synthesis*
  • Phosphinic Acids / pharmacology
  • Protein Conformation
  • Staphylococcus aureus / enzymology*
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Phosphinic Acids
  • Peptide Synthases
  • UDP-N-acetylmuramoyl-L-alanyl-D-glutamyl-lysine ligase
  • UDP-N-acetylmuramoylalanine-D-glutamate ligase