Yl. Hong et al., INHIBITION OF RECOMBINANT PNEUMOCYSTIS-CARINII DIHYDROPTEROATE SYNTHETASE BY SULFA DRUGS, Antimicrobial agents and chemotherapy, 39(8), 1995, pp. 1756-1763
Forty-four sulfa drugs were screened against crude preparations of rec
ombinant Pneumocystis carinii dihydropteroate synthetase. The apparent
Michaelis-Menten constants (K-m) for p-aminobenzoic acid and 7,8-dihy
dro-6-hydroxymethylpterin pyrophosphate were 0.34 +/- 0.02 and 2.50 +/
- 0.71 mu M, respectively. Several sulfa drugs, including sulfathiazol
e, sulfachlorpyridazine, sulfamethoxypyridazine, and sulfathiourea, in
hibited dihydropteroate synthetase approximately as well as sulfametho
xazole, as determined by the concentrations which cause 50% inhibition
and/or by K-i. For all sulfones and sulfonamides tested, unsubstitute
d p-amino groups were necessary for activity, and sulfonamides contain
ing an N-1-heterocyclic substituent were found to be the most effectiv
e inhibitors. Folate biosynthesis in isolated intact P. carinii was ap
proximately equally sensitive to inhibition by sulfamethoxazole, sulfa
chlorpyridazine, sulfamethoxypyridazine, sulfisoxazole, and sulfathiaz
ole. Two of these drugs, sulfamethoxypyridazine and sulfisoxazole, are
known to be less toxic than sulfamethoxazole and should be further ev
aluated for the treatment of P. carinii pneumonia.