Using
E. coli cells expressing different levels of tetracycline (TC) resistance. the relationship between the level of TC or minocycline (MINO) resistance and amount of drug accumulation inside the cells was analysed, and the following results were obtained.
1) Highly TC-resistant cells were moderately resistant to MINO and moderately TC-resistant cells were MINO sensitive.
2) For the same external drug concentration of 0.1 μg/ml, which did not inhibit the growth of any experimental cells, the higher the level of resistance to TC or MINO, the lower the accumulation of drug during the initial 30 minutes of incubation. The amount of accumulated TC with highly TC-resistant cells was half of that with TC-sensitive cells.
3) TC-sensitive, moderately TC-resistant, and highly TC-resistant cells could tolerate accumulated inside TC concentrations of 4, 20 and 150 μg/ml, respectively. In the case of MINO, highly TC-resistant cells could tolerate only 15 μg/ml.
4) Even when the inside concentration of TC reached a steady state, significant influx and efflux were still observed. During 30 min, 85% and 70% of accumulated TC was chased in TC-sensitive cells and highly TC-resistant cells, respectively.
5) When cells were simultaneously incubated with labeled TC and MINO, the accumulation of each drug was inhibited, indicating a common site of accumulation. TC had stronger affinity to the site.
Thus the mechanism of TC or MINO resistance involves not only a decreased rate of drug accumulation but also tolerance of the cell to the accumulated drugs. It was also assumed that TC resistance consists of two steps. One common to both TC and MINO, the other specific to TC.
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