Folic acid serves as a critical coenzyme for the synthesis of purines and ultimately DNA. In protozoa, as in bacteria, the active form of folic acid is produced in vivo by a simple two-step process. The first, the conversion of para-aminobenzoic acid to dihydrofolic acid, is blocked by sulfonamides. The second, the transformation of dihydro- to tetrahy-drofolic acid, is inhibited by folic acid analogs (folate antagonists), which competitively inhibit dihydrofolate reductase. Used together with sulfonamides, folate antagonists are very effective inhibitors of protozoan growth.
Trimethoprim, an inhibitor of dihydrofolate reductase, is used in combination with sulfamethoxazole to treat toxoplasmosis. Another folate antagonist, pyrimethamine, has a high affinity for sporozoan dihydrofolate reductase and has been particularly effective, when used with a sulfonamide, in the management of clinical malaria and toxoplasmosis.
In East Africa, a third folate antagonist, proguanil, is commonly taken in combination with chloroquine for malaria prophylaxis. Acquired protozoal resistance to folate antagonists is mutational and generally has been limited to particular species of malarial parasites.
Folate antagonists may result in folate deficiency in individuals with limited folatereserves, such as newborns, pregnant women, and the malnourished. This is of great concern when large doses are used for prolonged periods, as in the treatment of acute toxoplasmosis. When folate antagonists are used with sulfonamides, the entire range of sulfonamide toxic effects may be seen. Patients with AIDS appear to suffer an unusually high incidence of toxic side effects to trimethoprim–sulfamethoxazole.
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