Because of the increased appearance of vancomycin resistance in methicillin-resistant Staphylococcus aureus, and its consequences to hospital patients, it is of vital importance to understand the nature of this resistance and to develop effective inhibitors for treatment of infections. Vancomycin is used as the backup antibiotic for gram-positive infections which do not respond to penicillin therapy and for patients allegeric to penicillin.
Four specific aims are proposed: (1) determine x-ray structure of the Leuconostoc mesenteroides D-Ala:D-Lactate ligase, (2) determine the structure of F261Y mutant which exhibits a reversal of substrate specificity to produce D-alanine-D-alanine, (3) to generate a model of VanA, and (4) inhibitor design.
| Healy, V L; Lessard, I A; Roper, D I et al. (2000) Vancomycin resistance in enterococci: reprogramming of the D-ala-D-Ala ligases in bacterial peptidoglycan biosynthesis. Chem Biol 7:R109-19 |
| Fan, C; Park, I S; Walsh, C T et al. (1997) D-alanine:D-alanine ligase: phosphonate and phosphinate intermediates with wild type and the Y216F mutant. Biochemistry 36:2531-8 |
| Fan, C; Moews, P C; Shi, Y et al. (1995) A common fold for peptide synthetases cleaving ATP to ADP: glutathione synthetase and D-alanine:d-alanine ligase of Escherichia coli. Proc Natl Acad Sci U S A 92:1172-6 |
| Fan, C; Moews, P C; Walsh, C T et al. (1994) Vancomycin resistance: structure of D-alanine:D-alanine ligase at 2.3 A resolution. Science 266:439-43 |
