Evaluation of sulfa drugs against recombinant Pneumocystis carinii dihydropteroate synthetase and in vivo.

Sulfa drugs are potent and important anti-pneumocystis agents, but have a high incidence of adverse effects in AIDS patients. Although 15,000 sulfa drugs have been synthesized and dozens have been used in people, relatively few have been tested against P. carinii. In order to determine whether there are sulfa drugs which are better antipneumocystis agents than sulfamethoxazole and dapsone, we have been testing sulfa drugs in vitro, against recombinant P. carinii dihydropteroate synthetase, and in vivo. MATERIALS AND METHODS. Immunosuppression of latently infected rats, isolation of organisms, and enzyme and uptake assays were performed as previously described ( I ) . Rats were administered drug continuously via their drinking water for the full 6 weeks of immunosuppression. Exact doses were calculated by measuring daily water consumption. After 6 weeks, the rats were sacrificed, organisms were harvested, and the total number of cysts isolated from the lungs of each rat determined. Mice were treated either prophylactically or therapeutically as previously described (2). RESULTS AND DISCUSSION. Of the 44 sulfa drugs studied initially, 8 had ICSO's between 13 and 4 0 p M : sulfamethoxypyridazole, sulfathiazole, sulfachlorpyridazine, sulfamethoxypyridazine, sulfathiourea, sulfadimethoxine, sulfisoxazole, and sulfaquinoxaline. In general, we found that sulfonamides (Fig. 1) were more potent than sulfones. The compounds with greatest potency tended to have heterocyclic substituents on the N1 position (R1). Substituents on the p-amino group (R2) ablated activity (I).