{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:33:55Z","timestamp":1791920035389,"version":"4.3.4"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"13","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,4]]},"abstract":"<jats:p>\n                    Nifurtimox and benznidazole are the front-line drugs used to treat Chagas disease, the most important parasitic infection in the Americas. These agents function as prodrugs and must be activated within the parasite to have trypanocidal effects. Despite &gt;40 years of research, the mechanism(s) of action and resistance have remained elusive. Here, we report that in trypanosomes, both drugs are activated by a NADH-dependent, mitochondrially localized, bacterial-like, type I nitroreductase (NTR), and that down-regulation of this explains how resistance may emerge. Loss of a single copy of this gene in\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    , either through\n                    <jats:italic>in vitro<\/jats:italic>\n                    drug selection or by targeted gene deletion, is sufficient to cause significant cross-resistance to a wide range of nitroheterocyclic drugs. In\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    , loss of a single\n                    <jats:italic>NTR<\/jats:italic>\n                    allele confers similar cross-resistance without affecting growth rate or the ability to establish an infection. This potential for drug resistance by a simple mechanism has important implications, because nifurtimox is currently undergoing phase III clinical trials against African trypanosomiasis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0711014105","type":"journal-article","created":{"date-parts":[[2008,3,26]],"date-time":"2008-03-26T21:37:31Z","timestamp":1206567451000},"page":"5022-5027","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":405,"title":["A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes"],"prefix":"10.1073","volume":"105","author":[{"given":"Shane R.","family":"Wilkinson","sequence":"first","affiliation":[{"name":"*School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin C.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Horn","sequence":"additional","affiliation":[{"name":"Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Cheeseman","sequence":"additional","affiliation":[{"name":"Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,4]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(98)00037-1"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pctr.0010039"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.5.1733-1738.2004"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm050177"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.mi.27.100173.001533"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-002-0754-9"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)50687-6"},{"key":"e_1_3_3_8_2","first-page":"2184","article-title":"Breakage of bacterial DNA by nitrofuran derivatives","volume":"31","author":"McCalla DR","year":"1971","unstructured":"DR McCalla, A Reuvers, C Kaiser, Breakage of bacterial DNA by nitrofuran derivatives. 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