The relative growth inhibition caused by 12 tetracyclines in a susceptible strain of Staphylococcus aureus (111-elim) and in the same strain carrying a resistance-plasmid (111) showed entirely different patterns. For four of the tetracyclines (minocycline, anhydrotetracycline, chelocardin, and desdimethylaminotetracycline), the strain with the tetracycline plasmid (111) had virtually the same tolerance as the susceptible strain (111-elim). A resistant mutant of strain 111-elim showed a third pattern of relative growth inhibition, and another distinct pattern was observed in a veterinary wild strain of S. aureus. Of the 12 tetracyclines, 11 were effective inducers of higher tetracycline resistance in S. aureus 111, but no correlation was found between the efficacy of the tetracyclines as inducers and as inhibitors of growth of 111-elim or 111. At external drug concentrations causing doubling of the generation time (K1), 111-elim accumulated tetracycline, oxytetracycline, and minocycline to a degree corresponding to several thousand molecules per coccus. At a fixed external drug concentration, 111 accumulated less tetracycline and oxytetracycline than 111-elim, whereas comparison at their respective K1 values showed accumulation to be significantly higher for 111 than for 111-elim. The accumulation of tetracyclines is assumed to involve both surface sorption and active membrane transport. Resistance is probably due to decreased accumulation of the drugs, and a hypothesis explaining the mechanism of resistance is offered.Bacterial susceptibility to tetracyclines (Tcs) depends on the affinity of these drugs for at least two biological systems: the energydependent uptake mechanism (6, 9, 20) and the ribosomal protein-synthesizing machinery (13). Resistance may be obtained artificially by mutations influencing either of these systems (5, 15). In resistant wild strains of Staphylococcus aureus, two additional substances with affinity for Tc must be considered: the repressor of resistance (11,12,18) and the "resistance-antigen (1, 19).It seems reasonable to assume that relative affinities of these four systems for various Tcs may vary independently. As a result, significant variations in relative susceptibility of different strains of S. aureus to a series of Tcs may be expected. Moreover, the pattern of inhibitory effect of these Tcs on a susceptible bacterial strain, and on the same strain transfected with a resistance factor, might be different.These assumptions were examined in the present study in which the inhibitory activity of 12 Tcs on growth of susceptible and resistant strains and their influence on derepression of resistance were compared. For three of the Tcs, uptake was also investigated. MATERIALS AND METHODSBacterial strains. The Tc-resistant S. aureus strain 111 and the susceptible S. aureus strain 111-elim, obtained by elimination of the Tc plasmid, have been described (1,18,20