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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043412-05
Application #
6730566
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Peters, Kent
Project Start
2000-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2006-03-31
Support Year
5
Fiscal Year
2004
Total Cost
$348,552
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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