Effect of interaction between outer membrane permeability and beta-lactamase production on resistance to beta-lactam agents in gram-negative bacteria.

The effect of the interaction of beta-lactamase production and outer membrane permeability on the bacterial resistance to beta-lactam antibiotics was investigated using the Escherichia coli K12 substrains, which have outer membrane mutation and produce TEM-type penicillinase. Experiments confirmed that the cefazolin concentrations in the periplasm of cells exposed to the MIC were restricted to 2.4-4.6 microM among the bacteria, even though the MICs for the bacterial strains were distributed from 13 microM to 1,726 microM. The drug concentrations in the periplasm could be calculated on the basis of parameters obtained experimentally, and the calculated values were in fair agreement with the experimental values. The effect of beta-lactamase activity (Vmax/Km) and the outer membrane barrier on the elevation of MICs was observed to be synergistic, and the contribution of beta-lactamase was more effectively expressed in the bacterial cells with higher outer membrane barrier.