Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX

Bioorg Med Chem Lett. 2012 Jan 1;22(1):482-4. doi: 10.1016/j.bmcl.2011.10.094. Epub 2011 Nov 6.

Abstract

VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC(50) of 0.48-8.21mM. These data revealed a structure-activity relationship which is that the large substituent group on β-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / metabolism*
  • Carbon / chemistry
  • Chemistry, Pharmaceutical / methods
  • Dipeptides / chemistry*
  • Drug Design
  • Enterococcus / metabolism
  • Hydrogen-Ion Concentration
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Models, Chemical
  • Organophosphonates / chemistry*
  • Peptides / chemistry
  • Phosphorous Acids / chemistry*
  • Protein Binding
  • Serine-Type D-Ala-D-Ala Carboxypeptidase / metabolism*
  • Structure-Activity Relationship
  • Vancomycin Resistance / drug effects

Substances

  • Bacterial Proteins
  • Dipeptides
  • Organophosphonates
  • Peptides
  • Phosphorous Acids
  • phosphonic acid
  • Carbon
  • Serine-Type D-Ala-D-Ala Carboxypeptidase
  • VanX dipeptidase