title: A rational strategy for enhancing the affinity of vancomycin towards depsipeptide ligands.
abstract: Glycopeptide antibiotics with enhanced affinity for model depsipeptide ligands may also exhibit enhanced efficacy against bacteria exhibiting the vanA resistance phenotype. To design modified agents with enhanced affinity for these ligands, and better understand why traditional agents have low affinity for depsipeptide ligands, free energy perturbation studies were performed on vancomycin derivatives by means of molecular dynamics simulation. The results suggest that modifications of the asparagine side chain on residue 3 of the antibiotic which enhance its hydrophobicity will enhance the affinity of glycopeptide antibiotics for depsipeptide ligands, and act synergistically with other modifications that enhance the efficacy of these agents against vanA-positive bacteria.
authors.affiliation: Department of Pharmacology, Johnson Research Foundation for Molecular Biophysics, University of Pennsylvania, 19104-6084, USA. axe@pharm.med.upenn.edu
authors.forename: P H
authors.initials: PH
authors.lastname: Axelsen
authors.forename: D
authors.initials: D
authors.lastname: Li
mesh_terms: D000409:Alanine / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D004352:Drug Resistance, Microbial; D019344:Lactic Acid / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D013816:Thermodynamics; D014640:Vancomycin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; D008024:Ligands; C115095:acetyl-alanyl-lactate; C031735:acetylalanylalanine; D019344:Lactic Acid; D014640:Vancomycin; D000409:Alanine