The goal of the proposed research is the development of new drugs for the treatment of resistant, gram-positive bacterial infections. For the past 40 years, vancomycin has been the antibiotic of last resort for gram-positive bacteria. Through exchange of genetic information, pathogenic bacteria, most notably strains of Enterococci and Staphylococci, have developed resistance to vancomycin and other members of this family of glycopeptide antibiotics, including eremomycin and teicoplanin. These glycopeptide antibiotics inhibit bacterial cell wall biosynthesis through interference of transglycosidation and transpeptidation of a peptidoglycan. One form of resistance results from a substitution of a D-alanine for a D-lactate in the peptidoglycan. Other forms of resistance have been observed but are less well characterized. Vancomycin and eremomycin appear to function as head-to- tail type dimers, associated through hydrogen bonding of their peptide backbones. The proposed research focuses on the role of the sugar components of vancomycin and eremomycin which are critical but remote from the peptidoglycan binding site. The research will establish how the sugars facilitate in vivo formation of covalent dimers while retaining the hydrogen bonding of their peptide backbones and how the difference in sugar stereochemistry in vancomycin and eremomycin affects covalent dimerization. Covalent dimers, which are actually drug metabolites, will be synthesized and evaluated against both vancomycin- sensitive and vancomycin-resistant gram-positive bacteria. Covalent dimers will also be studied with respect to interaction and reaction with bacterial cell wall targets in both sensitive and resistant bacteria. The research will provide a further understanding of how secondary metabolites of microorganisms are designed to function as antibiotics without being too toxic to the microorganism which creates them.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
1R03AI043994-01
Application #
2727013
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Heyse, Stephen P
Project Start
1998-12-01
Project End
2001-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309