Escherichia coli resistance to β-lactam antibiotics through a decrease in the affinity of a target for lethality

Abstract

CLINICAL isolates of bacteria that have gained resistance to β-lactam antibiotics (penicillins, cephalosporins and related compounds) often arise by the acquisition of a plasmid that produces a β-lactamase^1,2. An increase in β-lactamase activity has also been shown to cause resistance in some mutants isolated in the laboratory³. In other cases, β-lactamase activity is not the cause of resistance and, at least in Gram-negative bacteria, alteration of the cell envelope resulting in decreased penetration of the antibiotic to the targets responsible for lethality in the cytoplasmic membrane has been proposed^3,4. For several groups of antibiotics resistance has been shown to occur by a decrease in the affinity of the target for lethality for the antibiotic^5–9 but, although this mechanism has been suggested as a possible cause of resistance to β-lactam antibiotics, no examples have been reported. The lethality targets for β-lactam antibiotics in Escherichia coli have recently been identified and I report here the characterisation of a mutant that has gained resistance to some β-lactams by a decrease in the affinity of such a target.