{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:56:00Z","timestamp":1789692960415,"version":"4.0.1"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T00:00:00Z","timestamp":1702598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Toxoplasmosis is a common protozoan infection that can have severe outcomes in the immunocompromised and during pregnancy, but treatment options are limited. Recently, nucleotide metabolism has received much attention as a target for new antiprotozoal agents and here we focus on pyrimidine salvage by <jats:italic>Toxoplasma gondii<\/jats:italic> as a drug target. Whereas uptake of [<jats:sup>3<\/jats:sup>H]-cytidine and particularly [<jats:sup>3<\/jats:sup>H]-thymidine was at most marginal, [<jats:sup>3<\/jats:sup>H]-uracil and [<jats:sup>3<\/jats:sup>H]-uridine were readily taken up. Kinetic analysis of uridine uptake was consistent with a single transporter with a K<jats:sub>m<\/jats:sub> of 3.3 \u00b1 0.8 \u00b5M, which was inhibited by uracil with high affinity (K<jats:sub>i<\/jats:sub> = 1.15 \u00b1 0.07 \u00b5M) but not by thymidine or 5-methyluridine, showing that the 5-Me group is incompatible with uptake by <jats:italic>T. gondii<\/jats:italic>. Conversely, [<jats:sup>3<\/jats:sup>H]-uracil transport displayed a K<jats:sub>m<\/jats:sub> of 2.05 \u00b1 0.40 \u00b5M, not significantly different from the uracil K<jats:sub>i<\/jats:sub> on uridine transport, and was inhibited by uridine with a K<jats:sub>i<\/jats:sub> of 2.44 \u00b1 0.59 \u00b5M, also not significantly different from the experimental uridine K<jats:sub>m<\/jats:sub>. The reciprocal, complete inhibition, displaying Hill slopes of approximately -1, strongly suggest that uridine and uracil share a single transporter with similarly high affinity for both, and we designate it uridine\/uracil transporter 1 (TgUUT1). While TgUUT1 excludes 5-methyl substitutions, the smaller 5F substitution was tolerated, as 5F-uracil inhibited uptake of [<jats:sup>3<\/jats:sup>H]-uracil with a K<jats:sub>i<\/jats:sub> of 6.80 \u00b1 2.12 \u00b5M (<jats:italic>P<\/jats:italic> &amp;gt; 0.05 compared to uracil K<jats:sub>m<\/jats:sub>). Indeed, we found that 5F-Uridine, 5F-uracil and 5F,2\u2019-deoxyuridine were all potent antimetabolites against <jats:italic>T. gondii<\/jats:italic> with EC<jats:sub>50<\/jats:sub> values well below that of the current first line treatment, sulfadiazine. <jats:italic>In vivo<\/jats:italic> evaluation also showed that 5F-uracil and 5F,2\u2019-deoxyuridine were similarly effective as sulfadiazine against acute toxoplasmosis. Our preliminary conclusion is that TgUUT1 mediates potential new anti-toxoplasmosis drugs with activity superior to the current treatment.<\/jats:p>","DOI":"10.3389\/fcimb.2023.1320160","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T10:58:26Z","timestamp":1702637906000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Pyrimidine salvage in Toxoplasma gondii as a target for new treatment"],"prefix":"10.3389","volume":"13","author":[{"given":"Hamza A. 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