INTERACTION OF PNEUMOCYSTIS-CARINII DIHYDROPTEROATE SYNTHASE WITH SULFONAMIDES AND DIAMINODIPHENYL SULFONE (DAPSONE)

Dihydropteroate synthase is the target enzyme for the sulfonamide comp ounds, which are the mainstay of therapy for Pneumocystis carinii pneu monia, a common infection in patients with impaired immunity. The stab ility of this enzyme, its kinetic constants with respect to substrates , and the 50% inhibitory concentration (IC50) of several sulfonamides and the sulfone dapsone have been characterized using both cell-free a nd intact organism assay systems. Stability of the enzyme is dependent on storage temperature, reducing reagents, and to a lesser extent, pr otease inhibitors. The sulfonamides sulfadiazine and sulfamethoxazole were found to be highly potent inhibitors of P. carinii dihydropteroat e synthase with IC(50)s of 0.42 and 0.71 mu M, respectively. Dapsone h ad equivalent potency when compared with the most potent sulfonamides tested in both assay systems. Data suggest that sulfamethoxazole, sulf adiazine, and dapsone may represent equivalent choices as P. carinii d ihydropteroate synthase inhibitors, assuming an equivalent in vivo dru g exposure can be achieved.