{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T23:40:17Z","timestamp":1778542817860,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,25]],"date-time":"2022-06-25T00:00:00Z","timestamp":1656115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R21\/R33 AI 119782"],"award-info":[{"award-number":["R21\/R33 AI 119782"]}]},{"name":"National Institute of Health","award":["P30DK058404"],"award-info":[{"award-number":["P30DK058404"]}]},{"name":"National Institute of Health","award":["P30CA068485"],"award-info":[{"award-number":["P30CA068485"]}]},{"name":"Vanderbilt University Medical Center","award":["R21\/R33 AI 119782"],"award-info":[{"award-number":["R21\/R33 AI 119782"]}]},{"name":"Vanderbilt University Medical Center","award":["P30DK058404"],"award-info":[{"award-number":["P30DK058404"]}]},{"name":"Vanderbilt University Medical Center","award":["P30CA068485"],"award-info":[{"award-number":["P30CA068485"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Trypanosoma brucei, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt Acanthamoeba sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) that can equally target T. brucei. We found that CHT\/ERGT inhibited cell growth in vitro, yielding EC50 values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered T. brucei cell morphology and death rapidly within hours. Notably, in vivo ERGT\/CHT protected mice infected with T. brucei, doubling their survival time following daily treatment for 8\u201310 days at 50 mg\/kg or 100 mg\/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development.<\/jats:p>","DOI":"10.3390\/molecules27134088","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T21:01:41Z","timestamp":1656277301000},"page":"4088","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Steroidal Antimetabolites Protect Mice against Trypanosoma brucei"],"prefix":"10.3390","volume":"27","author":[{"given":"Minu","family":"Chaudhuri","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ujjal K.","family":"Singha","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boden H.","family":"Vanderloop","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuj","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. David","family":"Nes","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1017\/S0031182010000946","article-title":"A spectrum of disease in Human African trypanosomiasis: The host and parasite genetics of virulence","volume":"137","author":"Sternberg","year":"2010","journal-title":"Parasitology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Silvester, E., McWilliam, K., and Matthews, K. (2017). The Cytological Events and Molecular Control of Life Cycle Development of Trypanosoma brucei in the Mammalian Bloodstream. 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