Nonspecific Ionic Inhibition of Ethambutol Binding by Mycobacterium smegmatis

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Magnesium sulfate and spermidine were tested for their effects on binding of 14C-ethambutol by Mycobacterium smegmatis. Concentrations were used that protected the organism from ethambutol inhibition. Sodium salts were examined as possible ethambutol antagonists to test the previously reported specificity of the divalent cation salt effect. Consistent with growth-protection experiments, 20 mM MgSO4 or 2.0 mM spermidine prevented and reversed 14C binding by cells shaken with 0.2 μg of 14C-ethambutol per ml of Sauton medium at 37 C. Sodium salts were not effective ethambutol antagonists when tested at 20 mM, but at concentrations equivalent in ionic strength (μ) to that provided by 20 mM MgSO4 they were effective. Thus, 20 mM MgSO4, 80 mM NaCl, or 27 mM Na2SO4 (μ = 0.08) all gave similar results in growth protection and binding experiments, suggesting that MgSO4 antagonism is a nonspecific ionic effect. Because spermidine (μ ≤ 0.012) antagonized ethambutol at an ionic strength substantially less than that required for the metal salts, its effect may hinge on structural similarity to ethambutol rather than its cationic character. Drug and polyamine may compete for one site or a heterogeneous group of binding sites involving adsorption, transport, and intracellular target reactions. Until we know at which of these levels spermidine antagonizes ethambutol binding, the relationship between polyamines and ethambutol action will remain obscure. However, these studies have weakened the earlier argument for a divalent cation-requiring system as a specific ethambutol target site.

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