ON THE MODE OF ACTION OF THE SULFONAMIDES II. THE SPECIFIC ANTAGONISM BETWEEN METHIONINE AND THE SULFONAMIDES IN ESCHERICHIA COLI

¹ From the Departments of Pediatrics and Biochemistry, Physiology and Pharmacology, Duke University School of Medicine, Durham, North Carolina

1. Methionine is an antagonist for the action of sulfanilamide, sulfapyridine, sulfadiazine and sulfathiazole on E. coli. This action is not due to a nonspecific stimulation of growth.

2. Methionine, unlike p-aminobenzoic acid, is effective only against low concentrations of the sulfonamides and does not exhibit a simple relationship in the concentrations necessary to antagonize increasing amounts of the sulfonamides.

3. The locus affected by methionine is one of the first to be inhibited by sulfonamide both in the point of time of contact and in the concentration of drug required.

4. Specificity is shown in the chemical and optical configuration. l(–) methionine is at least ten times as potent as the isomer and no other related compound carries activity.

5. Ethionine, norleucine and norvaline inhibit the growth of E. coli in simple media. This inhibition is due to competition with methionine.

6. Methionine is neither oxidized, decarboxylated nor deaminated by E. coli. It preserves the resting respiration of the cell, decreases the induction period when growth begins, and stimulates the synthesis of active respiratory enzymes.

7. A unified theory is presented to account for the actions of the known antagonists of the sulfonamides. Methionine is an antagonist because the sulfonamides, at low concentrations, act primarily by inhibiting the synthesis of methionine. This synthesis is dependent upon the presence of p-amino benzoic acid.