Development of extended-spectrum activity in TEM β-lactamases in hyper-mutable, mutS Escherichia coli

TEM-1 and TEM(pUC19)beta-lactamases can gain activity against ceftazidime and other expanded-spectrum cephalosporins via point mutation. The frequency of emergent resistance to ceftazidime at 4 x MIC was elevated >or= 250-fold in hyper-mutable, MutS-deficient Escherichia coli harbouring these beta-lactamase genes on high- or low-copy plasmids. Moreover, although ceftazidime-resistant mutants, or those with reduced susceptibility, were selected in both the wild-type and mutS hosts, many more mutants in the mutS host showed ceftazidimase-type extended-spectrum beta-lactamase (ESBL) activity. This correlated with a G-A point mutation at position 484 in the bla(TEM-1) and bla(TEM-pUC19) genes, conferring the Arg164His amino-acid substitution found in the TEM-29 ESBL. Non-ESBL mutants lacked changes in bla(TEM).