The evolution of beta-lactamases.

beta-lactamases, the enzymes often associated with resistance to beta-lactam antibiotics, are found in most bacterial species. Although these enzymes protected bacteria from naturally occurring beta-lactams long before the introduction of synthetic antimicrobial agents, the numbers and varieties of beta-lactamases have increased dramatically with the introduction of modern penicillins and cephalosporins. Over the past twenty years it has become apparent that families of beta-lactamases have been selected as the result of antimicrobial usage. Outbreaks of beta-lactam-resistant bacteria can be traced to the introduction of specific classes of beta-lactams or to the introduction of a specific agent. Many of the most serious epidemics can be related to transferable beta-lactamase genes that are harboured on multidrug-resistant plasmids. The separation of beta-lactamases into three major functional groups or four structural classes has been proposed. Stepwise selection of variants within several of these classes has been documented both in the clinical setting and in the laboratory, e.g. the extended-spectrum (TEM and SHV) beta-lactamases and the inhibitor-resistant (TEM) beta-lactamases. Close relationships among the recently described plasmid-mediated 'cephamycinases' and the common chromosomal cephalosporinases have been identified. Carbapenem-hydrolysing metallo-beta-lactamases with broad spectrum hydrolysing activity have become serious concerns as they begin to be described on plasmids. Factors contributing to selection of beta-lactam-resistant strains include decreased outer membrane permeability and increased beta-lactamase production.