Genetic diversity of drug targets including dihydropteroate synthase, dihydrofolate reductase and cytochrome b, in Pneumocystis carinii f. sp. hominis isolates in Japan.
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.
Takahashi
Takashi
T
Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. taka2si@kanazawa-med.ac.jp
Kanda
Tsugiyasu
T
Iwamoto
Aikichi
A
D019943:Amino Acid Substitution; D000890:Anti-Infective Agents / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D045303:Cytochromes b / Q000235:genetics*; D004094:Dihydropteroate Synthase / Q000235:genetics*; D006801:Humans; D007564:Japan; D009154:Mutation / Q000235:genetics; D045363:Pneumocystis carinii / Q000235:genetics*; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy / Q000382:microbiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D017211:Treatment Failure; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use
D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D045303:Cytochromes b; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase