{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:01:00Z","timestamp":1790690460104,"version":"4.1.0"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2000,4,1]],"date-time":"2000-04-01T00:00:00Z","timestamp":954547200000},"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":[[2000,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            There is a pressing need for drugs effective against the opportunistic protozoan pathogen\n            <jats:italic>Cryptosporidium parvum<\/jats:italic>\n            . Folate metabolic enzymes and enzymes of the thymidylate cycle, particularly dihydrofolate reductase (DHFR), have been widely exploited as chemotherapeutic targets. Although many DHFR inhibitors have been synthesized, only a few have been tested against\n            <jats:italic>C. parvum<\/jats:italic>\n            . To expedite and facilitate the discovery of effective anti-\n            <jats:italic>Cryptosporidium<\/jats:italic>\n            antifolates, we have developed a rapid and facile method to screen potential inhibitors of\n            <jats:italic>C. parvum<\/jats:italic>\n            DHFR using the model eukaryote,\n            <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n            . We expressed the DHFR genes of\n            <jats:italic>C. parvum<\/jats:italic>\n            ,\n            <jats:italic>Plasmodium falciparum<\/jats:italic>\n            ,\n            <jats:italic>Toxoplasma gondii<\/jats:italic>\n            ,\n            <jats:italic>Pneumocystis carinii<\/jats:italic>\n            , and humans in the same DHFR-deficient yeast strain and observed that each heterologous enzyme complemented the yeast DHFR deficiency. In this work we describe our use of the complementation system to screen known DHFR inhibitors and our discovery of several compounds that inhibited the growth of yeast reliant on the\n            <jats:italic>C. parvum<\/jats:italic>\n            enzyme. These same compounds were also potent or selective inhibitors of the purified recombinant\n            <jats:italic>C. parvum<\/jats:italic>\n            DHFR enzyme. Six novel lipophilic DHFR inhibitors potently inhibited the growth of yeast expressing\n            <jats:italic>C. parvum<\/jats:italic>\n            DHFR. However, the inhibition was nonselective, as these compounds also strongly inhibited the growth of yeast dependent on the human enzyme. Conversely, the antibacterial DHFR inhibitor trimethoprim and two close structural analogs were highly selective, but weak, inhibitors of yeast complemented by the\n            <jats:italic>C. parvum<\/jats:italic>\n            enzyme. Future chemical refinement of the potent and selective lead compounds identified in this study may allow the design of an efficacious antifolate drug for the treatment of cryptosporidiosis.\n          <\/jats:p>","DOI":"10.1128\/aac.44.4.1019-1028.2000","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T10:06:42Z","timestamp":1027764402000},"page":"1019-1028","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":34,"title":["Identification of\n            <i>Cryptosporidium parvum<\/i>\n            Dihydrofolate Reductase Inhibitors by Complementation in\n            <i>Saccharomyces cerevisiae<\/i>"],"prefix":"10.1128","volume":"44","author":[{"given":"Victoria Hertle","family":"Brophy","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Department of Genetics, University of Washington, Seattle, Washington 98195-73601;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Vasquez","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Division of Infectious Diseases, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California 94143-08112;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard G.","family":"Nelson","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Division of Infectious Diseases, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California 94143-08112;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Forney","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-51003; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Rosowsky","sequence":"additional","affiliation":[{"name":"<!--label omitted: 4-->Dana-Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 021154"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol Hopkins","family":"Sibley","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Department of Genetics, University of Washington, Seattle, Washington 98195-73601;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.170.7.3301-3304.1988"},{"key":"e_1_3_2_3_2","unstructured":"Ausubel\n              F. 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