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Biophysical Study of the Mode of Action of the Tetracycline Antibiotics

1965; Elsevier BV; Volume: 54; Issue: 10 Linguagem: Inglês

10.1002/jps.2600541006

1520-6017

John L. Colaizzi, Adelbert M. Knevel, Alfred N. Martin,

Enzyme function and inhibition

A considerable amount of evidence indicates that the tetracyclines may produce their antibiotic action by inhibition of metalloflavoenzymes.In this investigation the inhibitory properties of a series of biologically active and inactive tetracycline analogs on the metalloflavoenzyme, NADH-cytochrome c oxidoreductase, were investigated.Those analogs capable of inhibiting the enzyme appeared to act, at least partially, by chelation of enzyme-bound metal.The site of chelation on the tetracycline molecule a peared to be the C-11 to C-12 chromophore, or the C-1, C-2, C-3 region involving tge 2-carboxamide group of the tetracycline molecule.Both modification of the 2-carboxamide substituent and epimerization of the 4-dimethylamino group resulted in loss of inhibitory effect.This parallels known structureantibiotic activity relationships for these compounds.Inactive isotetracycline, tetracycline methiodide, and dedimethylaminotetracycline were able to inhibit the enzyme at least as well as the parent tetracyclines.These compounds might lack antibiotic activity due to inability to enter bacterial cells.N 1950, LOOMIS (1) observed that 7-chloro-tetracycline1 uncoupled mammalian aerobic phosphorylation, thus inhibiting the formation of ATP,2 which is the primary source of energy for cellular functions.This observation suggested that tetracyclines might act by inhibiting the action of important components of the electron transport system and the process of oxidative phosphorylation.It was also found by several workers (2, 3) that divalent metal ions could reverse the tetracycline-induced inhibition of oxidative phosphorylation in mammalian mitochondria, and as a result of these findings, it was postulated (4) that the tetracyclines uncouple oxidative phosphorylation by interacting with metal bound to an enzyme without actually removing it.In 1952, Miura et al. (5) showed that tetracyclines inhibit oxidative phosphorylation in intact bacteria at concentrations of approximately M. In conjunction with this finding, it is of interest that metal ions can neutralize the antibiotic effects of tetracyclines in bacteria cultures (6, 7) and that this effect does not appear to be simply a result of removal of the drug by complex formation (4).Many of these findings correlated with