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Current treatment options are limited in number and associated with severe side effects. Thus, novel anti-toxoplasma agents need to be identified and developed. 1-Deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) is considered the rate-limiting enzyme in the non-mevalonate pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate in the parasite, and has been previously investigated for its key role as a novel drug target in some species, encompassing Plasmodia, Mycobacteria and Escherichia coli. In this study, we present the first crystal structure of T. gondii DXR (TgDXR) in a tertiary complex with the inhibitor fosmidomycin and the cofactor NADPH in dimeric conformation at 2.5\u2005\u00c5 resolution revealing the inhibitor binding mode. In addition, we biologically characterize reverse \u03b1-phenyl-\u03b2-thia and \u03b2-oxa fosmidomycin analogues and show that some derivatives are strong inhibitors of TgDXR which also, in contrast with fosmidomycin, inhibit the growth of T. gondii in vitro. Here, ((3,4-dichlorophenyl)((2-(hydroxy(methyl)amino)-2-oxoethyl)thio)methyl)phosphonic acid was identified as the most potent anti T. gondii compound. These findings will enable the future design and development of more potent anti-toxoplasma DXR inhibitors.<\/jats:p>","DOI":"10.1042\/bcj20240110","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T14:59:37Z","timestamp":1722956377000},"page":"1075-1096","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["1-Deoxy-<scp>d<\/scp>-xylulose 5-phosphate reductoisomerase as target for anti <i>Toxoplasma gondii<\/i> agents: crystal structure, biochemical characterization and biological evaluation of inhibitors"],"prefix":"10.1042","volume":"481","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1429-230X","authenticated-orcid":false,"given":"Flaminia","family":"Mazzone","sequence":"first","affiliation":[{"name":"1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University, D\u00fcsseldorf, Germany"},{"name":"2University Hospital D\u00fcsseldorf, D\u00fcsseldorf, 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Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Wesemann","sequence":"additional","affiliation":[{"name":"6Institute of Biochemistry, Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Kurz","sequence":"additional","affiliation":[{"name":"4Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sander H.J.","family":"Smits","sequence":"additional","affiliation":[{"name":"3Center for Structural Studies, Heinrich Heine University, D\u00fcsseldorf, Germany"},{"name":"6Institute of Biochemistry, Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5652-6330","authenticated-orcid":false,"given":"Klaus","family":"Pfeffer","sequence":"additional","affiliation":[{"name":"1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University, D\u00fcsseldorf, Germany"},{"name":"2University Hospital D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"volume-title":"The Protozoan Phylum Apicomplexa: Volume 2","year":"2018","key":"2024082202130460800_BCJ-2024-0110C1"},{"key":"2024082202130460800_BCJ-2024-0110C2","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1016\/j.pt.2019.07.001","article-title":"Toxoplasma gondii","volume":"35","year":"2019","journal-title":"Trends 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