title: Development of extended-spectrum activity in TEM beta-lactamases in hyper-mutable, mutS Escherichia coli.
abstract: 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).
authors.affiliation: Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, London, UK. matthew.ellington@hpa.org.uk
authors.forename: M J
authors.initials: MJ
authors.lastname: Ellington
authors.forename: D M
authors.initials: DM
authors.lastname: Livermore
authors.forename: T L
authors.initials: TL
authors.lastname: Pitt
authors.forename: L M C
authors.initials: LM
authors.lastname: Hall
authors.forename: N
authors.initials: N
authors.lastname: Woodford
mesh_terms: D002442:Ceftazidime / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D051719:MutS DNA Mismatch-Binding Protein / Q000235:genetics*; D009154:Mutation; D001618:beta-Lactamases / Q000235:genetics*
chemical_list: D029968:Escherichia coli Proteins; D002442:Ceftazidime; D001618:beta-Lactamases; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli