title: From "An Enzyme Able to Destroy Penicillin" to Carbapenemases: 70 Years of Beta-lactamase Misbehaviour.
abstract: As early as 1940, Abraham and Chain described "an enzyme able to destroy penicillin". In the late 1940's, penicillin-resistant strains of Staphylococcus aureus were found to be a clinical problem. They produced a penicillinase that could hydrolyze the amide bond in the β-lactam ring. Later, an enzyme mediated by an R-factor was isolated from Enterobacteriaceae. Methicillin and cephalosporins, both very poor substrates of the S. aureus enzyme, were found to be sensitive to this new enzyme. Third generation cephalosporins appeared to solve the problem, but further enzymes were selected that exhibited extended spectra and could for instance hydrolyze cefotaxime and/or ceftazidime. The discovery of carbapenems constituted a major advance for our antimicrobial arsenal: they inactivated most of the essential penicillin binding proteins effectively and escaped the activity of nearly all known -β lactamases. However, the metallo-β-lactamases, which had not been recognised as a major danger before 1990, were found to act as effective carbapenemases and started to spread in a worrying way. Moreover, carbapenem-hydrolyzing enzymes were found in each of the 3 classes of active-site serine β-lactamases.
authors.affiliation: CIP, Université de Liège, B6- Sart-Tilman, 4000 Liège-Belgium. jmfrere@ulg.ac.be.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Frère
authors.forename: Eric
authors.initials: E
authors.lastname: Sauvage
authors.forename: Frédéric
authors.initials: F
authors.lastname: Kerff
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D001426:Bacterial Proteins / Q000378:metabolism; D015780:Carbapenems / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery / Q000266:history; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D008958:Models, Molecular; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D001618:beta-Lactamases; C063912:carbapenemase