Abstract

To provide information for the design of non-beta-lactam drugs which will bypass beta-lactam resistance mechanisms, we have begun an x-ray crystallographic study to establish the three-dimensional structure of E. coli D-alanine:D-alanine ligase, a cell wall synthesizing enzyme which is a potential drug target already well characterized biochemically and kinetically by other workers. From this D-amino acid ligase has evolved VanA, the newly-discovered enzyme responsible for an emerging enterococcal resistance to antibiotics of the vancomycin family. VanA is an altered ligase which has 45-52% sequence similarity with two DD-ligases we have crystallized. High-resolution crystallographic determination of the DD-ligase structure will therefore not only provide atomic-level information about a new target enzyme unique to bacteria, but will also provide a structure on which to build a three-dimensional model of the vancomycin resistance protein, which has so far been recalcitrant to x-ray structure analysis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034330-02
Application #
2069446
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1993-09-01
Project End
1996-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of Connecticut
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269