{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T06:33:41Z","timestamp":1771050821551,"version":"3.50.1"},"reference-count":29,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2010,2,1]],"date-time":"2010-02-01T00:00:00Z","timestamp":1264982400000},"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":[[2010,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Human African trypanosomiasis, caused by the\n            <jats:italic>Trypanosoma brucei<\/jats:italic>\n            protozoan parasite, is fatal when left untreated. Current therapies are antiquated, and there is a need for new pharmacologic agents against\n            <jats:italic>T. brucei<\/jats:italic>\n            targets that have no human ortholog. Trypanosomes have a single mitochondrion with a unique mitochondrial DNA, known as kinetoplast DNA (kDNA), a topologically complex network that contains thousands of interlocking circular DNAs, termed minicircles (\u223c1 kb) and maxicircles (\u223c23 kb). Replication of kDNA depends on topoisomerases, enzymes that catalyze reactions that change DNA topology.\n            <jats:italic>T. brucei<\/jats:italic>\n            has an unusual type IA topoisomerase that is dedicated to kDNA metabolism. This enzyme has no ortholog in humans, and RNA interference (RNAi) studies have shown that it is essential for parasite survival, making it an ideal drug target. In a large chemical library screen, two compounds were recently identified as poisons of bacterial topoisomerase IA. We found that these compounds are trypanocidal in the low micromolar range and that they promote the formation of linearized minicircles covalently bound to protein on the 5\u2032 end, consistent with the poisoning of mitochondrial topoisomerase IA. Surprisingly, however, band depletion studies showed that it is topoisomerase II\n            <jats:sub>mt<\/jats:sub>\n            , and not topoisomerase IA\n            <jats:sub>mt<\/jats:sub>\n            , that is trapped. Both compounds are planar aromatic polycyclic structures that intercalate into and unwind DNA. These findings reinforce the utility of topoisomerase II\n            <jats:sub>mt<\/jats:sub>\n            as a target for development of new drugs for African sleeping sickness.\n          <\/jats:p>","DOI":"10.1128\/aac.01025-09","type":"journal-article","created":{"date-parts":[[2009,12,15]],"date-time":"2009-12-15T03:19:21Z","timestamp":1260847161000},"page":"620-626","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Newly Identified Antibacterial Compounds Are Topoisomerase Poisons in African Trypanosomes"],"prefix":"10.1128","volume":"54","author":[{"given":"Sonya C.","family":"Tang","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa A.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"36","volume":"11","year":"2004","unstructured":"Abramoff, M. 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H., and P. Svingen. 1999. Immunoblot analysis and band depletion assays, p. 253-268. In M. Bjornsti and N. Osheroff (ed.), DNA topoisomerase protocols,vol. 1. DNA topology and enzymes. Humana Press Inc., Totowa, NJ.","journal-title":"DNA topoisomerase protocols"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M505977200"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2005.06.008"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.58.070189.002031"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.8.2066"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00344a015"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00344a014"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.06087.x"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.3.950"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)84979-7"},{"key":"e_1_3_2_25_2","first-page":"149","year":"2001","unstructured":"Shen, L. L. 2001. 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