Development of beta-lactamase inhibitors.
The resistance of bacteria to beta-lactam antibiotics was first associated with the production of the enzyme beta-lactamase as long ago as 1940. Since then, increasing numbers of beta-lactamase-producing bacteria capable of inactivating penicillins and cephalosporins have been isolated clinically. One approach to the problem posed by beta-lactamase-producing bacteria has been to seek substances that function as inhibitors of beta-lactamase and that can be used to protect beta-lactam antibiotics from destruction by the bacterial enzymes. The first clinically available inhibitor was clavulanic acid, a metabolite of Streptomyces clavuligerus that was identified in a screening program for naturally occurring beta-lactamase inhibitors. Clavulanic acid is a potent inhibitor of many bacterial beta-lactamases and has been formulated with amoxicillin and ticarcillin to produce broad-spectrum antibiotic combinations active against beta-lactamase-producing bacteria. After the discovery of clavulanic acid, various compounds have been reported to function as inhibitors of bacterial beta-lactamases, but only sulbactam and its prodrug, sultamicillin, have become available commercially. The success of clavulanic acid has confirmed beta-lactamase inhibitors as one solution to the problem of antibiotic-resistant bacteria.
Sutherland
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Beecham Pharmaceuticals Research Division, Betchworth, Surrey, England.
D000667:Ampicillin / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D019818:Clavulanic Acid; D002969:Clavulanic Acids / Q000494:pharmacology*; D004359:Drug Therapy, Combination / Q000494:pharmacology; D015507:Drugs, Investigational; D006801:Humans; D010406:Penicillins / Q000494:pharmacology*; D013407:Sulbactam / Q000494:pharmacology; D013982:Ticarcillin / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
D002969:Clavulanic Acids; D015507:Drugs, Investigational; D010406:Penicillins; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; C035444:sultamicillin; D000667:Ampicillin; C043215:ticarcillin-clavulanic acid; D013982:Ticarcillin; D013407:Sulbactam