The Molecular Basis of an Inhibition by Tetracyclines

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Abstract
The pyruvate-consuming system of Aerobacter aerogenes, which is inhibited by bacteriostatic concentrations of tetracyclines in an unaerated mineral salt medium, was isolated as a cell-free extract. The isolated system was inhibited by bacteriostatic concentrations of 8 tetracyclines. The inhibitory molecular form of each of these tetracyclines, all of which were acids releasing either 2 or 3 protons successively in aqueous solution, was the 1st dissociation product. Quantitatively the inhibition was directly dependent on the concentration of the inhibitory form of the antibiotic present. The tetracyclines tested were derived structurally from tetracycline by changes of the group attached at position 5, 6 or 7 (type a), a de-(dimethylamino) tetracycline (type b) and anhydrotetracycline. None of the tetracyclines was inhibitory in the absence of free magnesium ions. In the presence of micromolar concentrations of these ions, the inhibitory form of the tetracycline competed with flavine mono-nucleotide: the effectiveness of different tetracyclines as inhibitors of unaerated cultures correlated with the stability constants of postulated tetracycline-magnesium-enzyme complexes. The intracellu-lar concentrations of tetracyclines in organisms of sensitive and resistant strains were determined by measurements of inhibition of the pyruvate-consuming system. In medium containing bacteriostatic concentrations of types a and b tetracyclines, the intracellular concentrations of the sensitive organisms were the same as the extracellular concentrations. Anhydrotetracycline did not penetrate these organisms so readily. One of the resistant strains was insensitive because the tetracyclines did not penetrate into the organisms. There were no intracellular accumulations of tetracyclines from medium containing bacteriostatic concentrations. The bearing of these results on current theories to account for the bacteriostatic actions of tetracyclines is discussed.