Evidence that tetracycline analogs whose primary target is not the bacterial ribosome cause lysis of Escherichia coli

Abstract

The modes of action of atypical tetracyclines that do not directly inhibit bacterial protein synthesis were investigated. The analogs tested, chelocardin, anhydrotetracycline, 6-thiatetracycline, anhydrochlortetracycline, and 4-epi-anhydrochlortetracycline, were bactericidal and caused the lysis of Escherichia coli accompanied by the release of the cytoplasmic enzyme 1-galactosidase into the supernatant. Examination by electron microscopy demonstrated that cells exposed to these analogs underwent marked morphological alterations that included the formation of numerous ghosts and the appearance of cellular debris in the culture medium.Although atypical tetracyclines promoted lysis in intact organisms, they did not cause lysis of E. coli spheroplasts, indicating that the analogs do not directly destroy the cytoplasmic membrane. These agents may promote cell lysis and death by interfering with the membrane's electrochemical gradient, which in turn leads to stimulation of autolytic enzyme activity and cellular lysis. The results support recently published data which indicate that tetracyclines are divisible into two classes on the basis of their modes of action.

Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance

“…Nevertheless, it has now been established that the thiatetracyclines and a number of other tetracycline analogs, referred to collectively as atypical tetracyclines (43,44), exhibit a different structure-activity relationship from the majority of tetracyclines. These molecules, which also include the anhydrotetracyclines, 4-epi-anhydrotetracyclines, and chelocardin, appear to directly perturb the bacterial cytoplasmic membrane, leading to a bactericidal response (43,198,199). This contrasts with the typical tetracyclines, which interact with the ribosome to inhibit bacterial protein synthesis and display a reversible bacteriostatic effect.…”

“…Agents Chemother., abstr. 679, p. 199,1990). On further examination, the phenotype was not stably transferred and was most probably an artifact of the growth conditions (Jones et al, 30th ICAAC).…”

Low Doses of Tetracycline Trigger the E. coli Growth: A Case of Hormetic Response

“…The overall lack of literature concerning hormetic response in bacteria does not allow to speculate too much about the underlying mechanisms; experiments performed with the typical ribosome-inhibiting Tetracyclines, at doses by far higher than those causing the response we described, demonstrated that no morphological changes occur in E. coli cells (Oliva et al 1992). The mechanism underlying this kind of hormetic response, that is a time-limited enhancing of the number of bacterial cells, recalls an r-strategy reaction -and, indeed, E. coli is an r-strategist species -global regulation systems could therefore be activated in the presence of many, even unrelated kind of stresses including these very low antibiotic doses.…”

Evaluation of in vitro antibacterial activity of some disinfectants on Escherichia coli serotypes.

“…Chlorotetracycline is thought to interfere with bacterial membranes' electrochemical gradient, which led to the stimulation of autolytic enzyme activity and cellular lysis. The filamentation induced by tetracycline before lysis could have been caused by a direct inhibitory action on DNA synthesis, as explained by Oliva et al (1992).…”