Microbial kinetics and dependencies of individual and combined antibiotic inhibitors of protein biosynthesis.

Abstract

The generation rate constants for the steady-state growth of antibiotic-inhibited Escherichia coli have the same formal dependency on concentration for deoxylincomycin, lincomycin (phase I), erythromycin, clindamycin, and U24729A. They may be kinetically classified as a group A, in which the first three compounds comprise a subgroup A(1) and the latter two a subgroup A(2). Generation rate constants initially decrease linearly with concentration but asymptotically approach zero at higher concentrations. With tetracycline or chloramphenicol, the generation rate decreases linearly with all concentrations, and these compounds may be kinetically classified as group B. Combining an antibiotic from group A with one from group B gives a response equal to that obtained with equivalent amounts of each antibiotic alone, and there are no significant effects from the order of antibiotic addition. However, combinations of an A(1) with an A(2) antibiotic are antagonistic, and there are significant effects from the order of addition. The dependencies of generation rate constants in the presence of these antibiotics can be rationalized by a receptor site model that considers varying degrees of the rate of drug transfer and drug inactivation in the organism.