title: Direct interaction of a vancomycin derivative with bacterial enzymes involved in cell wall biosynthesis.
abstract: BACKGROUND
  The glycopeptide antibiotic vancomycin complexes DAla-DAla termini of bacterial cell walls and peptidoglycan precursors and interferes with enzymes involved in murein biosynthesis. Semisynthetic vancomycins incorporating hydrophobic sugar substituents exhibit efficacy against DAla-DLac-containing vancomycin-resistant enterococci, albeit by an undetermined mechanism. Contrasting models that invoke either cooperative dimerization and membrane anchoring or direct inhibition of bacterial transglycosylases have been proposed to explain the bioactivity of these glycopeptides.
  
  
  RESULTS
  Affinity chromatography has revealed direct interactions between a semisynthetic hydrophobic vancomycin (DCB-PV), and select Escherichia coli membrane proteins, including at least six enzymes involved in peptidoglycan assembly. The N(4)-vancosamine substituent is critical for protein binding. DCB-PV inhibits transglycosylation in permeabilized E. coli, consistent with the observed binding of the PBP-1B transglycosylase-transpeptidase.
  
  
  CONCLUSIONS
  Hydrophobic vancomycins interact directly with a select subset of bacterial membrane proteins, suggesting the existence of discrete protein targets. Transglycosylase inhibition may play a role in the enhanced bioactivity of semisynthetic glycopeptides.
authors.affiliation: Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. ranabir@merck.com
authors.forename: R
authors.initials: R
authors.lastname: Sinha Roy
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Kodali
authors.forename: Y
authors.initials: Y
authors.lastname: Xiong
authors.forename: R M
authors.initials: RM
authors.lastname: Kim
authors.forename: P R
authors.initials: PR
authors.lastname: Griffin
authors.forename: H R
authors.initials: HR
authors.lastname: Onishi
authors.forename: J
authors.initials: J
authors.lastname: Kohler
authors.forename: L L
authors.initials: LL
authors.lastname: Silver
authors.forename: K
authors.initials: K
authors.lastname: Chapman
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000032:analysis / Q000378:metabolism*; D002473:Cell Wall / Q000201:enzymology*; D002846:Chromatography, Affinity; D004926:Escherichia coli / Q000201:enzymology; D006031:Glycosylation / Q000187:drug effects; D010457:Peptidoglycan / Q000096:biosynthesis / Q000378:metabolism; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010457:Peptidoglycan; D014640:Vancomycin; D010458:Peptidyl Transferases