Effect of pyrimethamine on folic acid metabolism in Streptococcus faecalis and Escherichia coli.

Pyrimethamine (Daraprim (Burroughs Wellcome) ; 2,4diamino-5-p-chlorophenyl-6-ethylpyrimidine) is used in the treatment and prevention of malaria (1). When used in combination with one of the sulfonamides, it is also effective in the treatment of toxoplasmosis (2) and coccidiosis (3). Pyrimethamine is one of a series of 2,4-diaminopyrimidines which have been shown to be antagonists of folic acid and citrovorum factor (formyltetrahydrofolic acid) for the growth of Lactobacillus casei (4). In Streptococcus faecalis the inhibition by pyrimethamine is reversed only at low concentrations by folic acid; citrovorum factor was much more effective as a reversing agent (4). Thus growth inhibition reversal studies would presumably classify pyrimethamine as an antifolic acid drug similar to amethopterin. However, it was believed that a study of the action of pyrimethamine on a system divorced from growth was desirable in order to understand more fully its mechanism of action. The ultimate aim of these studies will be to determine the means by which resistance may develop to the action of the antifolic acid drugs. The experiments described in this paper were carried out with washed-cell suspensions and cell-free extracts of S. fuecalis. It has been demonstrated that pyrimethamine is a potent inhibitor of the conversion of folic acid to citrovorum factor in these systems. The inhibition has been found to be of the noncompetitive type and to involve the endogenous conversion of folic acid to citrovorum factor rather than the assimilation of folic acid by the cells. In addition, the effect of pyrimethamine on the synthesis of folic acid from p-aminobenzoic acid has been invcstigatrd.