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Tetrahydrofolate (FAH 4) participates in biosynthetic reactions that are vital to cellular growth and survival. In microorganisms, dihydrofolate (FAH2) is synthesized de novo from p-aminobenzoic acid. In mammals, folic acid (FA), FAH2 and FAH4 are assimilated from food. In all species FAH4 is reoxidized to FAH2 in the synthesis of thymidylate, and the enzyme, dihydrofolate reductase, is essential to the maintenance of FAH4 pools. Trimethoprim (TMP) selectively inhibits microbial reductases, but its effectiveness is strikingly enhanced when the synthesis of FAH2 is simultaneously blocked by sulfamethoxazole (SMZ). The combination, TMP-SMZ, has a broader spectrum of antimicrobial activity, is more rapidly bactericidal, and is less susceptible to the development of resistance, than either of the component drugs.
George H. Hitchings (Thu,) studied this question.