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Extended-spectrum TEM β-lactamases (ESBLs) do not usually confer resistance to β-lactamase inhibitors such as clavulanate or tazobactam. To investigate the compatibility of the two phenotypes we used site-directed mutagenesis of thebla TEM-1 gene to introduce into the TEM-1 β-lactamase amino acid substitutions that confer the ESBL phenotype: TEM-12 (Arg164→Ser), TEM-26 (Arg164→Ser plus Glu104→Lys), TEM-19 (Gly238→Ser), and TEM-15 (Gly238→Ser plus Glu104→Lys). These were combined with three sets of substitutions that confer inhibitor resistance: TEM-31 (Arg244→Cys), TEM-33 (Met69→Leu), and TEM-35 (Met69→Leu and Asn276→Asp). Introduction of the Arg244→Cys substitution gave rise to inhibitor-resistant hybrid enzymes that either lost ESBL activity (TEM-12, TEM-15, and TEM-19) or had reduced activity (TEM-26) against ceftazidime. In contrast, the introduction of Met69→Leu or Met69→Leu plus Asn276→Asp substitutions did not significantly affect the abilities of the enzymes to confer resistance to ceftazidime, although increased susceptibility to cefotaxime was observed withEscherichia coli strains that expressed the TEM-19 and TEM-26 β-lactamases. With the exception of the TEM-12 β-lactamase, introduction of the Met69→Leu substitution did not give rise to enzymes with increased resistance to clavulanate compared to that of the TEM-1 β-lactamase. However, introduction of the double substitution Met69→Leu plus Asn276→Asp in the ESBLs did give rise to low-level (TEM-19, TEM-15, and TEM-26) or moderate-level (TEM-12) clavulanate resistance. None of the hybrid enzymes were as resistant to clavulanate as the corresponding inhibitor-resistant TEM β-lactamase mutant, suggesting that active-site configuration in the ESBLs limits the degree of clavulanate resistance conferred.

antimicrobial agents and chemotherapy

Construction and Characterization of Mutants of the TEM-1 β-Lactamase Containing Amino Acid Substitutions Associated with both Extended-Spectrum Resistance and Resistance to β-Lactamase Inhibitors