STUDIES ON THE NATURE OF RESISTANCE OF GRAM-NEGATIVE BACILLI TO PENICILLIN : ANTAGONISTIC AND ENHANCING EFFECTS OF AMINO ACIDS.

The susceptibility of E. coli and Salmonella to penicillin is highest in a basal medium devoid of amino acids. Blood serum in certain concentrations, meat infusion broth, yeast extract, and casein hydrolysate interfere with the penicillin activity. The effect is apparently due to the antagonism of certain amino acids in the materials. Dicarboxyl-monoamino acids (i.e. aspartic, glutamic, and hydroxyglutamic acids and asparagine) cystine, arginine, histidine, and hydroxyproline are capable of suppressing the effect of penicilhn upon Gram-negative organisms. The antagonism of amino acids is not primarily related to their effect upon the rate of bacterial growth. It is suggested from the experiments detailed, that the antipenicillin activity is due to the effect of the amino acids upon bacterial metabolism. Prepassages in media of various concentrations of antagonistic amino acids alter the resistance of E. coli to penicillin. The changes are in inverse relation to the concentration of the antagonists. The antipenicillin activity of amino acids may be reversed significantly by dl-methionine. The substance, however, reverses only incompletely the antagonism of materials of mixed composition; i.e., casein hydrolysate, meat infusion broth, and serum. Upon addition of methionine, methionine sulfoxide, and threonine, there occurs a marked enhancement of penicillin susceptibility of broth cultures of Brucella, Eberthella, Salmonella, and Shigella. The enhancement is apparently due to the ability of this amino acid mixture to reverse effectively the action of the antagonists present in the cultures. Methionine is essential for the enhancement of penicillin susceptibility. Threonine and methionine sulfoxide facilitate the effect of methionine following a reciprocal quantitative relationship.