A retrospective view of beta-lactamases

The discovery of a penicillinase (later shown be a beta-lactamase) 50 years ago in Oxford came from the thought that the resistance of many Gram-negative bacteria to Fleming's penicillinase might be due to their production of a penicillin-destroying enzyme. The emergence of penicillinase-producing staphylococci in the early 1950s, particularly in hospitals, raised the question whether the medical value of penicillin would decline. The introduction of new semi-synthetic penicillins and cephalosporins in the 1960s began to reveal many beta-lactamases distinguishable by their different substrate profiles. In this period it was established that genes encoding beta-lactamases from Gram-negative bacilli could be carried from one organism to another on plasmids and also that penicillin inhibited a transpeptidase involved in bacterial cell wall synthesis. During the last two decades a number of these enzymes have been purified and the genes encoding them have been cloned. Much has now been learned, with the aid of powerful modern techniques, about their structures, their active sites, their relationship to penicillin-sensitive proteins in bacteria and to their likely evolution. Further knowledge may contribute to a more rational approach to chemotherapy in this area. Experience suggests that a need for new substances will continue.