{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:52:27Z","timestamp":1790517147901,"version":"4.1.0"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2010,7,1]],"date-time":"2010-07-01T00:00:00Z","timestamp":1277942400000},"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":[[2010,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection\n                    <jats:italic>in vitro<\/jats:italic>\n                    by exposure to increasing concentrations of nifurtimox,\n                    <jats:italic>Trypanosoma brucei brucei<\/jats:italic>\n                    nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (\u223c27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.\n                  <\/jats:p>","DOI":"10.1128\/aac.00332-10","type":"journal-article","created":{"date-parts":[[2010,5,3]],"date-time":"2010-05-03T21:57:40Z","timestamp":1272923860000},"page":"2893-2900","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":123,"title":["Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis"],"prefix":"10.1128","volume":"54","author":[{"given":"Antoaneta Y.","family":"Sokolova","sequence":"first","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Wyllie","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Patterson","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra L.","family":"Oza","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D.","family":"Read","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan H.","family":"Fairlamb","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(80)90035-2"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-4758(99)01414-3"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.2174\/1381612043383214"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/510534"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1472-8206.2003.00167.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1139\/m81-013"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm021030a"},{"key":"e_1_3_2_9_2","unstructured":"Delivering innovation and building a robust pipeline. 2009"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/6.2.223"},{"key":"e_1_3_2_11_2","first-page":"2471","volume":"45","year":"1986","unstructured":"Docampo, R., and S. 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