Targeting Bacterial Cell Wall Peptidoglycan Synthesis by Inhibition of Glycosyltransferase Activity

Chem Biol Drug Des. 2016 Feb;87(2):190-9. doi: 10.1111/cbdd.12662. Epub 2015 Oct 9.

Abstract

Synthesis of bacterial cell wall peptidoglycan requires glycosyltransferase enzymes that transfer the disaccharide-peptide from lipid II onto the growing glycan chain. The polymerization of the glycan chain precedes cross-linking by penicillin-binding proteins and is essential for growth for key bacterial pathogens. As such, bacterial cell wall glycosyltransferases are an attractive target for antibiotic drug discovery. However, significant challenges to the development of inhibitors for these targets include the development of suitable assays and chemical matter that is suited to the nature of the binding site. We developed glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors. In addition, we designed a library of disaccharide compounds based on the minimum moenomycin fragment with peptidoglycan glycosyltransferase inhibitory activity and based on a more drug-like and synthetically versatile disaccharide building block. A subset of these disaccharide compounds bound and inhibited the glycosyltransferase enzymes, and these compounds could serve as chemical entry points for antibiotic development.

Keywords: NMR spectroscopy; drug discovery; glycosyltransferase; penicillin-binding protein; transglycosylase.

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Cell Wall / metabolism*
  • Drug Design
  • Escherichia coli / enzymology
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation
  • Oligosaccharides / chemistry
  • Oligosaccharides / metabolism
  • Oligosaccharides / pharmacology
  • Penicillin-Binding Proteins / antagonists & inhibitors
  • Penicillin-Binding Proteins / metabolism
  • Peptidoglycan / biosynthesis*
  • Peptidoglycan Glycosyltransferase / antagonists & inhibitors*
  • Peptidoglycan Glycosyltransferase / metabolism
  • Protein Structure, Tertiary
  • Staphylococcus aureus / drug effects
  • Vancomycin / chemistry
  • Vancomycin / metabolism
  • Vancomycin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Oligosaccharides
  • Penicillin-Binding Proteins
  • Peptidoglycan
  • Vancomycin
  • Peptidoglycan Glycosyltransferase
  • moenomycin