Conformational and quantitative characterization of oritavancin-peptidoglycan complexes in whole cells of Staphylococcus aureus by in vivo 13C and 15N labeling

J Mol Biol. 2006 Apr 7;357(4):1253-62. doi: 10.1016/j.jmb.2006.01.040. Epub 2006 Jan 30.

Abstract

Solid-state NMR has been used to examine the cell walls of intact whole cells of Staphyloccus aureus grown on media containing D-[1-(13)C]alanine, [(15)N]glycine, and the alanine racemase inhibitor, alaphosphin. The results of in situ site-selective, four-frequency NMR experiments show directly for the first time that (i) 54% of the cell-wall peptidoglycan stems have D-alanine termini and 46%, D-alanine-D-alanine termini; (ii) the molar ratio of stems ending in D-alanine to esterified alditol repeats of cell-wall teichoic and lipoteichoic acids is 3:2; and (iii) 50% of the mature cell-wall binding sites for a fluorinated oritavancin analogue consist of two nearest-neighbor peptide stems of different glycan strands. The drug is bound to the D-Ala-D-Ala terminus of one stem and is proximate to the bridging pentaglycyl segment that cross-links the two stems. Structural details of the binding site are revealed in a model of the glycopeptide-peptidoglycan interaction produced by molecular dynamics simulations with internuclear distance restraints determined by NMR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / metabolism
  • Binding Sites
  • Carbon Isotopes / chemistry*
  • Carbon Isotopes / metabolism
  • Cell Wall / chemistry
  • Glycopeptides / chemistry*
  • Glycopeptides / metabolism
  • Lipoglycopeptides
  • Models, Molecular
  • Molecular Structure
  • Nitrogen Isotopes / chemistry*
  • Nitrogen Isotopes / metabolism
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptidoglycan / chemistry*
  • Peptidoglycan / metabolism
  • Staphylococcus aureus / chemistry*
  • Staphylococcus aureus / metabolism

Substances

  • Anti-Bacterial Agents
  • Carbon Isotopes
  • Glycopeptides
  • Lipoglycopeptides
  • Nitrogen Isotopes
  • Peptidoglycan
  • oritavancin