title: Beta-lactamase inactivation by mechanism-based reagents.
abstract: The mechanistic pathway followed by the E. coli RTEM beta-lactamase has been studied with a view to clarifying the mode of action of a number of recently discovered inactivators of the enzyme. There is clear evidence that the beta-lactamase-catalysed hydrolysis of the 7-alpha-methoxycephem, cefoxitin, proceeds via an acyl-enzyme intermediate. An analysis of the inactivation reactions of all the known beta-lactam derivatives that result in irreversible loss of enzyme activity permits the identification of three structural features required for a beta-lactamase inactivator. The application of these principles suggests a new group of mechanism-based inactivators of the enzyme: the sulphones of N-acyl derivatives of 6-beta-aminopenicillanic acid that are themselves poor substrates for the enzyme. These sulphones are powerful inactivators of the beta-lactamase.
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000201:enzymology; D019818:Clavulanic Acid; D007769:Lactams; D010397:Penicillanic Acid / Q000494:pharmacology / Q000031:analogs & derivatives; D013407:Sulbactam / Q000031:analogs & derivatives; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: C028188:6-chloropenicillanic acid sulfone; D000900:Anti-Bacterial Agents; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D019818:Clavulanic Acid; C020786:olivanic acid; C018008:brobactam; D010397:Penicillanic Acid; D001618:beta-Lactamases; D013407:Sulbactam