title: 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.
authors.affiliation: Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. taka2si@kanazawa-med.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tsugiyasu
authors.initials: T
authors.lastname: Kanda
authors.forename: Aikichi
authors.initials: A
authors.lastname: Iwamoto
mesh_terms: 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
chemical_list: D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D045303:Cytochromes b; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase