Journal article
Vancomycin Binding to Low-Affinity Ligands: Delineating a Minimum Set of Interactions Necessary for High-Affinity Binding
Journal of medicinal chemistry, v 42(22), pp 4714-4719
04 Nov 1999
PMID: 10579833
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Bacterial resistance to vancomycin has been attributed to the loss of an intermolecular hydrogen bond between vancomycin and its peptidoglycan target when cell wall biosynthesis proceeds via depsipeptide intermediates rather than the usual polypeptide intermediates. To investigate the relative importance of this hydrogen bond to vancomycin binding, we have determined crystal structures at 1.0 Å resolution for the vancomycin complexes with three ligands that mimic peptides and depsipeptides found in vancomycin-sensitive and vancomycin-resistant bacteria: N-acetylglycine, d-lactic acid, and 2-acetoxy-d-propanoic acid. These, in conjunction with structures that have been reported previously, indicate higher-affinity ligands elicit a structural change in the drug not seen with these low-affinity ligands. They also enable us to define a minimal set of drug−ligand interactions necessary to confer higher-affinity binding on a ligand. Most importantly, these structures point to factors in addition to the loss of an intermolecular hydrogen bond that must be invoked to explain the weaker affinity of vancomycin for depsipeptide ligands. These factors are important considerations for the design of vancomycin analogues to overcome vancomycin resistance.
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Details
- Title
- Vancomycin Binding to Low-Affinity Ligands: Delineating a Minimum Set of Interactions Necessary for High-Affinity Binding
- Creators
- Patrick J LollJeffrey KaplanBarry S SelinskyPaul H Axelsen
- Publication Details
- Journal of medicinal chemistry, v 42(22), pp 4714-4719
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000083519300023
- Scopus ID
- 2-s2.0-0033524010
- Other Identifier
- 991014878154504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal