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 sub stitution A237T slightly increased (from 24 to 32 mu g/ml) the cephalo thin MIC for Escherichia coli RYC1000 but did not influence the activi ties of cefotaxime, ceftazidime, and aztreonam (MICs of 0.03, 0.12, an d 0.06 mu g/ml, respectively), Despite its apparent neutrality, additi on of the A237T mutation to the pair of mutations characterizing TEM-I O (R164S and E240K) had a strong effect on substrate preference. Cefta zidime and aztreonam MICs decreased from 128 and 16 mu g/ml to 16 and 2 mu g/ml, respectively. In contrast, the cefotaxime MIC increased fro m 0.5 to 4 mu g/ml. The acquisition of apparently neutral or even dele terious mutations results in a very effective mechanism of resistance to different beta-lactams that may be simultaneously or subsequently p resent in the environment. We propose here that the mutation in positi on 237 is an example of a modulating mutation and that consideration o f this type of mutation may be important for understanding the evoluti on of beta-lactamases.