{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:13:58Z","timestamp":1791090838232,"version":"4.1.0"},"reference-count":20,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T00:00:00Z","timestamp":1359676800000},"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":[[2013,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n The nitroimidazole fexinidazole has potential as a safe and effective oral drug therapy for the treatment of visceral leishmaniasis. To date, nitroheterocyclics have not been used in the treatment of leishmaniasis, and relatively little is known about their mechanism of action. In African trypanosomes, nitro drugs are reductively activated by a type I nitroreductase (NTR), absent in mammalian cells. Modulation of nitroreductase levels in\n Trypanosoma brucei<\/jats:named-content>\n directly affected sensitivity to nitro compounds, with reduced concentrations of the enzyme leading to moderate nitro drug resistance. In view of the progression of fexinidazole into clinical development for visceral leishmaniasis, here we assess the essentiality of the nitroreductase in\n Leishmania donovani<\/jats:named-content>\n and the effect of modulating nitroreductase levels on susceptibility to fexinidazole. The failure to directly replace both endogenous copies of the\n NTR<\/jats:italic>\n gene, except in the presence of an ectopic copy of the gene, suggests that the\n NTR<\/jats:italic>\n gene is essential for the growth and survival of\n L. donovani<\/jats:named-content>\n promastigotes. Loss of a single chromosomal copy of the\n L. donovani NTR<\/jats:italic>\n gene resulted in parasites that were mildly resistant (<2-fold) to the predominant\n in vivo<\/jats:italic>\n metabolite of fexinidazole, while parasites overexpressing NTR were 18-fold more susceptible. These data confirm that\n Leishmania<\/jats:named-content>\n NTR plays a pivotal role in fexinidazole activation. Reliance on a single enzyme for prodrug activation may leave fexinidazole vulnerable to the emergence of drug resistance. However, the essentiality of the NTR in\n L. donovani<\/jats:named-content>\n promastigotes, combined with the limited resistance shown by\n NTR<\/jats:italic>\n single knockout cells, suggests that the potential for the spread of NTR-based resistance to fexinidazole may be limited.\n <\/jats:p>","DOI":"10.1128\/aac.01788-12","type":"journal-article","created":{"date-parts":[[2012,12,4]],"date-time":"2012-12-04T09:01:14Z","timestamp":1354611674000},"page":"901-906","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":56,"title":["Assessing the Essentiality of Leishmania donovani Nitroreductase and Its Role in Nitro Drug Activation"],"prefix":"10.1128","volume":"57","author":[{"given":"Susan","family":"Wyllie","sequence":"first","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, 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, 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, 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\/S0035-9203(03)80047-0"},{"key":"e_1_3_2_3_2","unstructured":"Regional Technical Advisory Group on Kala-azar Elimination. 2005. Report of the first meeting Manesar Haryana 20\u201323 December 2004. WHO project IND CDR 714. SEA-VBC-88. World Health Organization Regional Office for South-East Asia New Delhi India. http:\/\/www.searo.who.int\/LinkFiles\/Kala_azar_VBC-88.pdf."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728210903153862"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trstmh.2006.02.005"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61117-X"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00926669"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000923"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003326"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.230847"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711014105"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(03)00142-7"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.07.038"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST0330983"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2009.03.014"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00332-10"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.75.103004.142539"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10771"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jis331"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0169-4758(96)10055-7"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)62050-8"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01788-12","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01788-12","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T17:21:05Z","timestamp":1645464065000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01788-12"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2]]},"references-count":20,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2013,2]]}},"alternative-id":["10.1128\/AAC.01788-12"],"URL":"https:\/\/doi.org\/10.1128\/aac.01788-12","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2]]},"assertion":[{"value":"2012-08-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-11-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-01-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}