Back to Search
Start Over
Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate
- Source :
- Proceedings of the National Academy of Sciences. 100:5658-5663
- Publication Year :
- 2003
- Publisher :
- Proceedings of the National Academy of Sciences, 2003.
-
Abstract
- Bacterial transglycosylases are enzymes that couple the disaccharide subunits of peptidoglycan to form long carbohydrate chains. These enzymes are the target of the pentasaccharide antibiotic moenomycin as well as the proposed target of certain glycopeptides that overcome vancomycin resistance. Because bacterial transglycosylases are difficult enzymes to study, it has not previously been possible to evaluate how moenomycin inhibits them or to determine whether glycopeptide analogues directly target them. We have identified transglycosylase assay conditions that enable kinetic analysis of inhibitors and have examined the inhibition of Escherichia coli penicillin-binding protein 1b (PBP1b) by moenomycin as well as by various glycopeptides. We report that chlorobiphenyl vancomycin analogues that are incapable of binding substrates nevertheless inhibit E. coli PBP1b, which shows that these compounds interact directly with the enzyme. These findings support the hypothesis that chlorobiphenyl vancomycin derivatives overcome vanA resistance by targeting bacterial transglycosylases. We have also found that moenomycin is not competitive with respect to the lipid II substrate of PBP1b, as has long been believed. With the development of suitable methods to evaluate bacterial transglycosylases, it is now possible to probe the mechanism of action of some potentially very important antibiotics.
- Subjects :
- Penicillin binding proteins
Molecular Conformation
Muramoylpentapeptide Carboxypeptidase
Biology
medicine.disease_cause
Microbiology
chemistry.chemical_compound
Bacterial Proteins
Multienzyme Complexes
Vancomycin
Escherichia coli
medicine
Penicillin-Binding Proteins
Cloning, Molecular
Enzyme Inhibitors
Codon
chemistry.chemical_classification
Peptidoglycan glycosyltransferase
Multidisciplinary
Molecular Structure
Lipid II
Escherichia coli Proteins
Vancomycin Resistance
Biological Sciences
Serine-Type D-Ala-D-Ala Carboxypeptidase
Glycopeptide
Kinetics
Mutagenesis, Insertional
Enzyme
Hexosyltransferases
chemistry
Biochemistry
Peptidyl Transferases
Peptidoglycan Glycosyltransferase
Peptidoglycan
Carrier Proteins
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 100
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....b891cd79cfa599961ec33087fc6a3dc3