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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

Published on: October 25, 2013

Vancomycin derivative with damaged D-Ala-D-Ala binding cleft binds to cross-linked peptidoglycan in the cell wall of

Sung Joon Kim1, Shigeru Matsuoka, Gary J Patti

  • 1Department of Chemistry, Washington University, St. Louis, Missouri 63130, USA.

Biochemistry
|February 28, 2008
PubMed

Insights

Des-N-methylleucyl-4-(4-fluorophenyl)benzyl-vancomycin (DFPBV) retains antimicrobial activity by binding to Staphylococcus aureus cell walls via its hydrophobic side chain near a pentaglycyl bridge, not the typical d-Ala-d-Ala site.

Area of Science:

  • Microbiology
  • Biochemistry
  • Medicinal Chemistry

Background:

  • Vancomycin resistance in pathogens is a growing public health concern.
  • Des-N-methylleucyl-4-(4-fluorophenyl)benzyl-vancomycin (DFPBV) is a modified glycopeptide with activity against resistant strains.
  • The precise binding mechanism of DFPBV, especially its interaction with bacterial cell walls, remains incompletely understood.

Purpose of the Study:

  • To identify the in situ binding site of DFPBV within the cell walls of Staphylococcus aureus.
  • To elucidate the molecular interactions governing DFPBV's antimicrobial activity.
  • To investigate the role of secondary binding sites in glycopeptide efficacy.

Main Methods:

  • Solid-state nuclear magnetic resonance (NMR) spectroscopy was employed.
  • Staphylococcus aureus cell walls were isotopically labeled with d-[1-(13)C]alanine, [1-(13)C]glycine, and l-[epsilon-(15)N]lysine.
  • Rotational-echo double-resonance (REDOR) NMR was used to determine internuclear distances between the fluorine atom of DFPBV and the labeled cell wall components.

Main Results:

  • DFPBV was identified to bind to the peptidoglycan of Staphylococcus aureus as a monomer.
  • The vancosamine hydrophobic side chain of DFPBV was found to be positioned near a pentaglycyl bridge in the cell wall.
  • These findings indicate binding occurs at a secondary site, distinct from the canonical d-Ala-d-Ala binding cleft.

Conclusions:

  • DFPBV utilizes a secondary binding site involving the pentaglycyl bridge for interaction with Staphylococcus aureus cell walls.
  • This secondary binding site, in addition to potential primary interactions, contributes to the antimicrobial activity of DFPBV.
  • The study suggests that vancosamine-modified glycopeptides may rely on both stem-terminus and stem-bridge recognition for their efficacy against resistant pathogens.

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