A237T as a modulating mutation in naturally occurring extended-spectrum TEM-type beta-lactamases.
A TEM-1 beta-lactamase derivative containing the single amino acid substitution A237T slightly increased (from 24 to 32 microg/ml) the cephalothin MIC for Escherichia coli RYC1000 but did not influence the activities of cefotaxime, ceftazidime, and aztreonam (MICs of 0.03, 0.12, and 0.06 microg/ml, respectively). Despite its apparent neutrality, addition of the A237T mutation to the pair of mutations characterizing TEM-10 (R164S and E240K) had a strong effect on substrate preference. Ceftazidime and aztreonam MICs decreased from 128 and 16 microg/ml to 16 and 2 microg/ml, respectively. In contrast, the cefotaxime MIC increased from 0.5 to 4 microg/ml. The acquisition of apparently neutral or even deleterious mutations results in a very effective mechanism of resistance to different beta-lactams that may be simultaneously or subsequently present in the environment. We propose here that the mutation in position 237 is an example of a modulating mutation and that consideration of this type of mutation may be important for understanding the evolution of beta-lactamases.
Blázquez
J
J
Servicio de Microbiología, Hospital Ramón y Cajal, Madrid, Spain. jesus.blazquez@hrc.es
Negri
M C
MC
Morosini
M I
MI
Gómez-Gómez
J M
JM
Baquero
F
F
D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics*; D005798:Genes, Bacterial / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D018440:beta-Lactam Resistance / Q000235:genetics; D001618:beta-Lactamases / Q000235:genetics*
D001618:beta-Lactamases; C034413:beta-lactamase TEM-1