{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:26:58Z","timestamp":1785403618005,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,11]]},"group-title":"Microbiology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01AI169846"],"award-info":[{"award-number":["R01AI169846"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AI144464"],"award-info":[{"award-number":["R01AI144464"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32AI060546"],"award-info":[{"award-number":["T32AI060546"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Toxoplasma gondii<\/jats:italic>\n                  is a protozoan parasite capable of infecting most warm-blooded animals, including humans, and can cause severe disease in immunocompromised individuals and the developing fetus. Current treatments for toxoplasmosis are effective only against the acute stage of infection and have limited or no activity against the latent bradyzoite stage found within tissue cysts. The mitochondrion of\n                  <jats:italic>T. gondii<\/jats:italic>\n                  is a validated drug target, and the clinically used drug atovaquone acts by inhibiting the mitochondrial electron transport chain (ETC) at the coenzyme Q:cytochrome c oxidoreductase (\n                  <jats:italic>\n                    bc\n                    <jats:sub>1<\/jats:sub>\n                  <\/jats:italic>\n                  complex). In this study, we evaluate two legacy 4(1\n                  <jats:italic>H<\/jats:italic>\n                  )-quinolones: ICI 56,780 and WR 243246, previously shown to inhibit the\n                  <jats:italic>\n                    Plasmodium falciparum bc\n                    <jats:sub>1<\/jats:sub>\n                  <\/jats:italic>\n                  complex, for their efficacy against\n                  <jats:italic>T. gondii<\/jats:italic>\n                  . Both compounds inhibit tachyzoite growth with low-nanomolar EC\u2085\u2080 values and disrupt parasite mitochondrial function by blocking cytochrome\n                  <jats:italic>c<\/jats:italic>\n                  reduction and collapsing the mitochondrial membrane potential. Notably, ICI 56,780 protects mice from lethal infection with type I RH tachyzoites. Importantly, ICI 56,780 also exhibits potent activity against chronic-stage parasites, reducing cyst size and bradyzoite viability\n                  <jats:italic>in vitro<\/jats:italic>\n                  and showing low-nanomolar EC\u2085\u2080 values against\n                  <jats:italic>in vivo<\/jats:italic>\n                  -derived bradyzoites. In mice chronically infected with\n                  <jats:italic>T. gondii<\/jats:italic>\n                  , treatment with ICI 56,780 significantly decreases brain cyst burden. Although these 4(1\n                  <jats:italic>H<\/jats:italic>\n                  )-quinolones display some pharmacokinetic limitations, our findings highlight their potential as promising chemotypes active against both acute and chronic stages of\n                  <jats:italic>T. gondii<\/jats:italic>\n                  and provide a framework for future medicinal chemistry efforts to improve drug-like properties while preserving or enhancing anti-bradyzoite activity.\n                <\/jats:p>","DOI":"10.64898\/2026.03.10.710892","type":"posted-content","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T02:30:22Z","timestamp":1773282622000},"source":"Crossref","is-referenced-by-count":0,"title":["Legacy 4(1\n                  <i>H<\/i>\n                  )-quinolone scaffolds activity against acute and chronic\n                  <i>Toxoplasma gondii<\/i>\n                  infection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8987-2937","authenticated-orcid":false,"given":"Melissa A.","family":"Sleda","sequence":"first","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8107-8798","authenticated-orcid":false,"given":"Khaly","family":"Diagne","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8627-9590","authenticated-orcid":false,"given":"Victoria M.","family":"Clifton","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology, University of Georgia, Athens, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1271-0187","authenticated-orcid":false,"given":"Baihetiya","family":"Baierna","sequence":"additional","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA"},{"name":"Department of Cellular Biology, University of Georgia, Athens, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7038-6867","authenticated-orcid":false,"given":"Roman","family":"Manetsch","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA"},{"name":"Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA"},{"name":"Center for Drug Discovery, Northeastern University, Boston, MA, USA"},{"name":"Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA, 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