Synthesis of bulky .beta.-lactams for inhibition of cell surface .beta.-lactamase activity

Procedures are described for the preparation of a series of compounds consisting of methicillin linked to beta-cyclodextrin through variable hydrophilic linkers. beta-Cyclodextrin was coupled to the antibiotic methicillin to prevent the antibiotic from permeating the outer membranes of bacteria. Sto...

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Bibliographic Details
Published in:Bioconjugate chemistry 1993-11, Vol.4 (6), p.434-439
Main Authors: Karunaratne, D. Nedra, Farmer, Susan, Hancock, Robert E. W
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - pharmacokinetics
Anti-Bacterial Agents - pharmacology
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
beta-Cyclodextrins
beta-Lactamase Inhibitors
Biological and medical sciences
Cell Membrane - enzymology
Cell Membrane Permeability
Chemistry, Pharmaceutical
Cyclodextrins - chemistry
Cyclodextrins - pharmacokinetics
Drug Carriers - chemistry
Medical sciences
Methicillin - chemistry
Methicillin - pharmacokinetics
Methicillin - pharmacology
Molecular Weight
Pharmacology. Drug treatments
Solubility
Water - chemistry
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Summary:Procedures are described for the preparation of a series of compounds consisting of methicillin linked to beta-cyclodextrin through variable hydrophilic linkers. beta-Cyclodextrin was coupled to the antibiotic methicillin to prevent the antibiotic from permeating the outer membranes of bacteria. Stoichiometric oxidation of the beta-cyclodextrin with sodium metaperiodate provided a functional group for coupling to the linker. Methicillin was coupled to the linker via its carboxyl group. These compounds were tested for activity toward purified beta-lactamase. The length of the spacer arm between beta-cyclodextrin and methicillin was crucial in binding beta-lactamase and inhibiting activity. Compounds with longer spacers were effective inhibitors of beta-lactamase. We have deduced that the length of the spacer should be greater than 16 A for optimum inhibition of beta-lactamase.
ISSN:1043-1802
1520-4812
DOI:10.1021/bc00024a004