{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:25:24Z","timestamp":1790915124995,"version":"4.1.0"},"reference-count":20,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2004,11,1]],"date-time":"2004-11-01T00:00:00Z","timestamp":1099267200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2004,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Most drugs used for prevention and treatment of\n            <jats:italic>Pneumocystis jirovecii<\/jats:italic>\n            pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of\n            <jats:italic>P. jirovecii<\/jats:italic>\n            drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in\n            <jats:italic>P. jirovecii<\/jats:italic>\n            DHFR from 33 patients diagnosed with\n            <jats:italic>P. jirovecii<\/jats:italic>\n            pneumonia who were receiving prophylaxis with a DHFR inhibitor (\n            <jats:italic>n<\/jats:italic>\n            = 15), prophylaxis without a DHFR inhibitor (\n            <jats:italic>n<\/jats:italic>\n            = 11), or no prophylaxis (\n            <jats:italic>n<\/jats:italic>\n            = 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18;\n            <jats:italic>P<\/jats:italic>\n            = 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that\n            <jats:italic>P. jirovecii<\/jats:italic>\n            populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to\n            <jats:italic>P. jirovecii<\/jats:italic>\n            drug resistance.\n          <\/jats:p>","DOI":"10.1128\/aac.48.11.4301-4305.2004","type":"journal-article","created":{"date-parts":[[2004,10,25]],"date-time":"2004-10-25T18:09:00Z","timestamp":1098727740000},"page":"4301-4305","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":82,"title":["Mutations of\n            <i>Pneumocystis jirovecii<\/i>\n            Dihydrofolate Reductase Associated with Failure of Prophylaxis"],"prefix":"10.1128","volume":"48","author":[{"given":"Aimable","family":"Nahimana","sequence":"first","affiliation":[{"name":"Hospital Preventive Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meja","family":"Rabodonirina","sequence":"additional","affiliation":[{"name":"Service de Parasitologie, Ho\u0302pital de la Croix-Rousse, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Bille","sequence":"additional","affiliation":[{"name":"Institute of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Francioli","sequence":"additional","affiliation":[{"name":"Hospital Preventive Medicine"},{"name":"Division of Infectious Diseases, University Hospital of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe M.","family":"Hauser","sequence":"additional","affiliation":[{"name":"Institute of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","unstructured":"AIDS\/WHO. 2000. Provisional WHO\/UNAIDS secretariat recommendations on the use of co-trimoxazole prophylaxis in adults and children living with HIV\/AIDS in Africa. UNAIDS Geneva Switzerland."},{"key":"e_1_3_2_3_2","first-page":"915","volume":"15","year":"1994","unstructured":"Champness, J. N., A. Achari, S. P. Ballantine, P. K. Bryant, C. J. Delves, and D. K. Stammers. 1994. The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 \u00c5 resolution. Structure15:915-924.","journal-title":"Structure"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi982728m"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0770"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.19.2450"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/17.12.1244"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/315148"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.11.3092-3096.2000"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.9.3101-3103.2002"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.4.1104-1108.2001"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.7.2610-2616.2004"},{"key":"e_1_3_2_13_2","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1111\/j.1550-7408.2003.tb00673.x","volume":"50","year":"2003","unstructured":"Nahimana, A., M. Rabodonirina, P. Francioli, J. Bille, and P. M. Hauser. 2003. Pneumocystis jirovecii dihydrofolate reductase polymorphisms associated with failure of prophylaxis. J. Eukaryot. Microbiol.50:656-657S.","journal-title":"J. Eukaryot. Microbiol."},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1086\/378239"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid0907.020753"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(00)00115-7"},{"key":"e_1_3_2_17_2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1089\/107662903765826723","volume":"9","year":"2003","unstructured":"Patel, O., J. Satchell, J. Baell, R. Fernley, P. Coloe, and I. Macreadie. 2003. Inhibition studies of sulfonamide-containing folate analogs in yeast. Microb. Drug Resist.9:139-146.","journal-title":"Microb. Drug Resist."},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-51-6-510"},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1054\/drup.1998.0060","volume":"2","year":"1999","unstructured":"Triglia, T., and A. F. Cowman. 1999. The mechanism of resistance to sulfa drugs in Plasmodium falciparum.Drug Resist. Update2:15-19.","journal-title":"Drug Resist. Update"},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1089\/mdr.1998.4.91","volume":"4","year":"1998","unstructured":"Vedantam, G., and B. P. Nichols. 1998. Characterization of a mutationally altered dihydropteroate synthase contributing to sulfathiazole resistance in Escherichia coli.Microb. Drug Resist.4:91-97.","journal-title":"Microb. 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