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. 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.
Karunaratne
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DN
Department of Microbiology, University of British Columbia, Vancouver, Canada.
Farmer
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S
Hancock
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RE
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry; D008712:Methicillin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008970:Molecular Weight; D012995:Solubility; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; D003505:Cyclodextrins; D004337:Drug Carriers; D047392:beta-Cyclodextrins; D065093:beta-Lactamase Inhibitors; D014867:Water; C031215:betadex; D008712:Methicillin