title: Ways to overcome cephalosporinase-mediated beta-lactam resistance in Enterobacter cloacae.
abstract: Beta-lactam antibiotics which affect mainly PBP 3 and are poor substrates for the cephalosporinase of Enterobacter cloacae, but tightly bind to it, are not active against cephalosporinase-overproducing variants of this organism. Attempts have been made to greatly reduce the affinity for the beta-lactamase in order to prevent both binding and hydrolysis. 3-Quaternary ammonium cephalosporins and some cephalosporin (S)-sulfoxides were seen to fit this requirement. Suitable substitution of the monocyclic beta-lactam nucleus also resulted in compounds with lower affinity than aztreonam. Temocillin, differing from ticarcillin by the 6-methoxy group, also has a lower affinity for the cephalosporinase. All compounds discussed retain the highest affinity for PBP 3 and are active against cephalosporinase-overproducing E. cloacae in contrast to compounds with high affinity for the cephalosporinase.
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002510:Cephalosporinase / Q000502:physiology*; D004352:Drug Resistance, Microbial; D004754:Enterobacter / Q000187:drug effects* / Q000201:enzymology; D004755:Enterobacteriaceae / Q000187:drug effects*; D006602:Hexosyltransferases; D006868:Hydrolysis; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000502:physiology*; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D002510:Cephalosporinase; D001618:beta-Lactamases