This is a proposal to apply the techniques of X-ray crystallography, molecular dynamics simulation, and infrared spectroscopy, with organic synthesis, in a coordinated interdisciplinary effort to better understand ligand recognition by glycopeptide antibiotics, and develop new agents effective against vancomycin-resistant bacteria.
We aim to determine the structure of ligand complexes with glycopeptide antibiotics using X-ray crystallography, experimentally verify aspects of ligand recognition behavior predicted by computer simulation, and synthetically alter the natural specificity of glycopeptide antibiotic in a way which enhances its affinity for cell wall fragments of vancomycin-resistant bacteria. We emphasize the use of molecular dynamics computer simulations for interpreting results and guiding experimental strategies. The overall aim is to confront the emerging health threat of vancomycin-resistance by facilitating the rational design of drugs, and gain insight into the physico-chemical basis of specific molecular recognition.
