Antibacterial structure-activity relationships obtained with resistant microorganisms I: Inhibition of R-factor...

Aparent partition coefficients and inhibitory activities against sensitive and resistant Escherichia coli were determined for 14 tetracyclines. The difference in the kinetics of inhibition of the two organisms is discussed in terms of their permeabilities. The partition coefficients were determined in an octanol-buffer system. Values for eight compounds were in general agreement with the literature; values for the remaining six compounds had not been reported previously. Growth of the organisms was determined by a single-point turbidimetric method in the presence and absence of tetracyclines. Inhibitory activities were obtained by a kinetic treatment. Derived rate constants for the sensitive organism were linearly related to antibiotic concentration. For the resistant organism and 12 compounds, the derived rate constants and antibiotic concentration were related in a manner typical of saturation kinetics. These inhibitory activities were related to the partition coefficients, while activities against the sensitive strain were not. These findings suggest that activity against the resistant strain is permeability controlled but that activity against the sensitive strain has a different rate-determining step.