Genetic diversity of drug targets including dihydropteroate synthase, dihydrofolate reductase and cytochrome b, in Pneumocystis carinii f. sp. hominis isolates in Japan.

Abstract

This study examined gene polymorphisms in dihydropteroate synthase (DHPS), dihydrofolate reductase (DHFR) and cytochrome b of Pneumocystis carinii isolated from 34 patients with P. carinii pneumonia (PCP) in Japan. Four amino acid substitutions (Thr55Ala, Pro57Ser, His60Gln and Glu169Gly) in DHPS, 2 mutations (Ala67Val and Cys166Tyr) in DHFR and 1 mutation (Leu280Phe) in cytochrome b were found in 9 (26.5%), 2 (5.9%) and 1 (2.9%) patient, respectively. No linkage of mutations in DHPS to those in DHFR or cytochrome b was observed. The patients whose isolates showed mutations in DHPS, DHFR and cytochrome b were not exposed to sulfonamides, DHFR inhibitors and atovaquone before they developed PCP, except for 2 patients. Co-trimoxazole treatment failed more frequently in patients whose isolates had DHPS mutations than in those whose isolates showed wild-type DHPS (n=6 [85.7%] versus n=3 [12.5%]; P=0.001). Our results suggest that DHPS mutations may contribute to failure of co-trimoxazole treatment for PCP.