Abstract
The glycopeptide antibiotics prevent maturation of the bacterial cell wall by binding to the terminal d-alanyl-d-alanine moiety of peptidoglycan precursors, thereby inhibiting the enzymes involved in the final stages of peptidoglycan synthesis. However, there are significant differences in the biological activity of particular glycopeptide derivatives that are not related to their affinity for d-Ala-d-Ala. We compare the ability of vancomycin and a set of clinically relevant glycopeptides to inhibit Staphylococcus aureus PBP2 (penicillin binding protein), the major transglycosylase in a clinically relevant pathogen, S. aureus. We report experiments suggesting that activity differences between glycopeptides against this organism reflect a combination of substrate binding and secondary interactions with key enzymes involved in peptidoglycan synthesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / metabolism
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Anti-Bacterial Agents / pharmacology*
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Dipeptides / chemistry
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Dipeptides / metabolism
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Kinetics
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Microbial Sensitivity Tests
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Penicillin-Binding Proteins / antagonists & inhibitors*
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Penicillin-Binding Proteins / chemistry
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Penicillin-Binding Proteins / metabolism
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / enzymology*
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Substrate Specificity
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Uridine Diphosphate N-Acetylmuramic Acid / analogs & derivatives*
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Uridine Diphosphate N-Acetylmuramic Acid / chemistry
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Uridine Diphosphate N-Acetylmuramic Acid / metabolism
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Vancomycin / chemistry
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Vancomycin / metabolism
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Vancomycin / pharmacology*
Substances
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Anti-Bacterial Agents
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Dipeptides
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Penicillin-Binding Proteins
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Uridine Diphosphate N-Acetylmuramic Acid
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muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol
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alanylalanine
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Vancomycin