{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:24:01Z","timestamp":1782865441014,"version":"3.54.5"},"reference-count":74,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009148","name":"Queen Mary University of London","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009148","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003971","name":"Islamic Development Bank","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Nitroheterocycles represent an important class of compound used to treat trypanosomiasis. They often function as prodrugs and can undergo type I nitroreductase (NTR1)\u2010mediated activation before promoting their antiparasitic activities although the nature of these downstream effects has yet to be determined. Here, we show that in an NTR1\u2010dependent process, benznidazole promotes DNA damage in the nuclear genome of <jats:italic>Trypanosoma brucei<\/jats:italic>, providing the first direct link between activation of this prodrug and a downstream trypanocidal mechanism. Phenotypic and protein expression studies revealed that components of the trypanosome\u2019s homologous recombination (HR) repair pathway (TbMRE11, \u03b3H2A, TbRAD51) cooperate to resolve the benznidazole\u2010induced damage, indicating that the prodrug\u2010induced lesions are most likely double stand DNA breaks, while the sequence\/recruitment kinetics of these factors parallels that in other eukaryotes HR systems. When extended to other NTR1\u2010activated 2\u2010nitroimidazoles, some were shown to promote DNA damage. Intriguingly, the lesions induced by these required TbMRE11 and TbCSB activities to fix leading us to postulate that TbCSB may operate in systems other than the transcription\u2010coupled nucleotide excision repair pathway. Understanding how existing trypanosomal drugs work will aid future drug design and help unlock novel reactions\/pathways that could be exploited as targets for therapeutic intervention.<\/jats:p>","DOI":"10.1111\/mmi.14763","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T13:05:29Z","timestamp":1622552729000},"page":"674-689","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Unraveling the antitrypanosomal mechanism of benznidazole and related 2\u2010nitroimidazoles: From prodrug activation to DNA damage"],"prefix":"10.1111","volume":"116","author":[{"given":"Ambika","family":"Dattani","sequence":"first","affiliation":[{"name":"School of Biological &amp; Chemical Sciences Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isatou","family":"Drammeh","sequence":"additional","affiliation":[{"name":"School of Biological &amp; Chemical Sciences Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishah","family":"Mahmood","sequence":"additional","affiliation":[{"name":"School of Biological &amp; Chemical Sciences Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahbubur","family":"Rahman","sequence":"additional","affiliation":[{"name":"School of Biological &amp; Chemical Sciences Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Szular","sequence":"additional","affiliation":[{"name":"School of Biological &amp; Chemical Sciences Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8474-1943","authenticated-orcid":false,"given":"Shane R.","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"School of Biological &amp; Chemical Sciences Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10771"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2005.08.009"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1179\/2047773213Y.0000000105"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201490041"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsos.170095"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6726a2"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006\u20102952(99)00264\u20106"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02046-12"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2014.01.002"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201014986\u20106"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25048"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2002.03122.x"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2019.04.009"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010019\u20101051\u20106"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01941187"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00456"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003\u20109861(79)90251\u20100"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2005.06.021"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/31.1.9"},{"key":"e_1_2_6_21_1","first-page":"19","article-title":"Mutagenicity of nifurtimox and benznidazole in the Salmonella\/microsome assay","volume":"19","author":"Ferreira R.C.","year":"1986","journal-title":"Brazilian Journal of Medical and Biological Research"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0008261"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsos.170773"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2012.01.008"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20102952(85)90684\u20107"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20102952(85)90514\u20103"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006875"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706734200"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.230847"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05135\u201011"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.2307\/3282883"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx00009a004"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020885"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473\u20103099(13)70002\u20101"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2018.04.008"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12589"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-23731-6"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0074\u201002762008000300008"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jis331"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-3305-4-169"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201205149"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky579"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.13767"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(17)32758\u20107"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2011.03.018"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003\u20109861(82)90383\u20106"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.4061\/2010\/840768"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867325666180426164352"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2014.04.003"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(17)31612\u20104"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01360\u201006"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.21839"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214\u2010109X(16)00047\u20104"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203205200"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432\u20101033.1997.00739.x"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2010.09.002"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prevetmed.2013.10.024"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2008.04.004"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1708\u20108305.2011.00576.x"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2008.04.009"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12973"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(02)00165-2"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166\u20106851(98)00127\u20103"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1358\/dot.2020.56.10.3161237"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002844"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2018.11.005"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006\u20102952(98)00324\u20104"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2016.05.009"},{"key":"e_1_2_6_69_1","first-page":"33","article-title":"Chagas disease in Latin America: an epidemiological update based on 2010 estimates","volume":"90","author":"WHO","year":"2015","journal-title":"Weekly Epidemiological Record"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802611796575894"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399409001252"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2005.06.022"},{"key":"e_1_2_6_73_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711014105"},{"key":"e_1_2_6_74_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.95.1.49"},{"key":"e_1_2_6_75_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkv376"}],"container-title":["Molecular Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/mmi.14763","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/mmi.14763","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/mmi.14763","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T14:47:42Z","timestamp":1692715662000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/mmi.14763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":74,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1111\/mmi.14763"],"URL":"https:\/\/doi.org\/10.1111\/mmi.14763","archive":["Portico"],"relation":{},"ISSN":["0950-382X","1365-2958"],"issn-type":[{"value":"0950-382X","type":"print"},{"value":"1365-2958","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,23]]},"assertion":[{"value":"2021-02-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}