Vancomycin: conformational consequences of the sugar substituent

Area of Science:

• Structural biology
• Medicinal chemistry
• Computational chemistry

Background:

• Vancomycin is a critical antibiotic for treating Gram-positive bacterial infections.
• Understanding vancomycin's structure-activity relationship is crucial for developing new antibiotics.
• Glycosylation is a key modification in many natural products with biological activity.

Purpose of the Study:

• To determine the high-resolution three-dimensional structures of vancomycin and aglyco-vancomycin in solution.
• To investigate the conformational flexibility and dynamics of these molecules.
• To elucidate the role of glycosylation in vancomycin's structure and potential activity.

Main Methods:

• Nuclear magnetic resonance (NMR) spectroscopy was used to obtain experimental data.
• Metric matrix distance geometry and molecular dynamics calculations were employed for structure determination.
• Ensemble-based calculations analyzed conformational flexibility on the NMR time scale.

Main Results:

• Two distinct conformational families were identified for vancomycin, differing in vancosamine substituent positioning.
• Aglyco-vancomycin adopted a single, stable conformation in solution.
• Differences in amide proton alignment and aromatic ring orientation were observed between vancomycin and aglyco-vancomycin.

Conclusions:

• High-resolution structural characterization reveals significant conformational differences between vancomycin and its deglycosylated form.
• These structural variations, particularly in the glycosylation pattern, may play a role in vancomycin's antibiotic efficacy.
• The findings provide insights into the molecular basis of vancomycin's interaction with bacterial cell-wall precursors.