{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T17:26:27Z","timestamp":1782840387393,"version":"3.54.5"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:00Z","timestamp":1658966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Chagas disease is an endemic American parasitosis, caused by<jats:italic>Trypanosoma cruzi<\/jats:italic>. The current therapies, benznidazole (BZN) and nifurtimox (NFX), show limited efficacy and multiple side effects. Thus, there is a need to develop new trypanocidal strategies. Ivermectin (IVM) is a broad-spectrum antiparasitic drug with low human and veterinary toxicity with effects against<jats:italic>T. brucei<\/jats:italic>and<jats:italic>Leishmania<\/jats:italic>spp. Considering this and its relatively low cost, we evaluate IVM as a potential repurposed trypanocidal drug on<jats:italic>T. cruzi<\/jats:italic>and other trypanosomatids. We found that IVM affected, in a dose-dependent manner, the proliferation of<jats:italic>T. cruzi<\/jats:italic>epimastigotes as well as the amastigotes and trypomastigotes survival. The Selectivity Index for the amastigote stage with respect to Vero cells was 12. The IVM effect was also observed in<jats:italic>Phytomonas jma 066<\/jats:italic>and<jats:italic>Leishmania mexicana<\/jats:italic>proliferation but not in<jats:italic>Crithidia fasciculata<\/jats:italic>. On the epimastigote stage, the IVM effect was trypanostatic at 50 \u03bcM but trypanocidal at 100 \u03bcM. The assays of the drug combinations of IVM with BNZ or NFX showed mainly additive effects among combinations.<jats:italic>In silico<\/jats:italic>studies showed that classical structures belonging to glutamate-gated Cl channels, the most common IVM target, are absent in kinetoplastids. However, we found in the studied trypanosomatid genomes one copy for putative IMP\u03b1 and IMP\u03b2, potential targets for IVM. The putative IMP\u03b1 genes (with 76% similarity) showed conserved Armadillo domains but lacked the canonical IMP\u03b2 binding sequence. These results allowed us to propose a novel molecular target in<jats:italic>T. cruzi<\/jats:italic>and suggest IVM as a good candidate for drug repurposing in the Chagas disease context.<\/jats:p>","DOI":"10.3389\/fcimb.2022.885268","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T08:17:25Z","timestamp":1658996245000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Broadening the spectrum of ivermectin: Its effect on Trypanosoma cruzi and related trypanosomatids"],"prefix":"10.3389","volume":"12","author":[{"given":"Laura","family":"Fraccaroli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Daniela","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia Gabriela","family":"Perdomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agustina Nicole","family":"Clausi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dar\u00edo Emmanuel","family":"Balcazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Larocca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Carrillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3791\/63210","article-title":"In vitro drug screening against all life cycle stages of trypanosoma cruzi using parasites expressing \u03b2-galactosidase","volume":"5","author":"Alonso","year":"2021","journal-title":"J. Vis. Exp."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-13-417","article-title":"Evaluation of ivermectin mass drug administration for malaria transmission control across different West African environments","volume":"13","author":"Alout","year":"2014","journal-title":"Malar. J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1021\/ci400284v","article-title":"Application of computer-aided drug repurposing in the search of new cruzipain inhibitors: Discovery of amiodarone and bromocriptine inhibitory effects","volume":"53","author":"Bellera","year":"2013","journal-title":"J. Chem. Inf. Model."},{"key":"B4","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1126\/science.6308762","article-title":"Ivermectin: a potent new antiparasitic agent","volume":"221","author":"Campbell","year":"1983","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1007\/s00436-018-5747-4","article-title":"Nuclear distribution of the trypanosoma cruzi RNA pol I subunit RPA31 during growth and metacyclogenesis, and characterization of its nuclear localization signal","volume":"117","author":"Canela-P\u00e9rez","year":"2018","journal-title":"Parasitol. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3899","DOI":"10.1007\/s00436-020-06885-z","article-title":"Trypanosoma cruzi importin \u03b1: ability to bind to a functional classical nuclear localization signal of the bipartite type","volume":"119","author":"Canela-P\u00e9rez","year":"2020","journal-title":"Parasitol. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.molbiopara.2019.02.003","article-title":"Nuclear localization signals in trypanosomal proteins","volume":"229","author":"Canela-P\u00e9rez","year":"2019","journal-title":"Mol. Biochem. Parasitol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1016\/S0140-6736(18)32613-8","article-title":"Advancing the repurposing of ivermectin for malaria","volume":"393","author":"Chaccour","year":"2019","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1113\/JP275236","article-title":"Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin","volume":"596","author":"Chen","year":"2018","journal-title":"J. Physiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/20367","article-title":"Structure of importin-beta bound to the IBB domain of importin-alpha","volume":"399","author":"Cingolani","year":"1999","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/ja.2017.11","article-title":"Ivermectin: enigmatic multifaceted \u2018wonder\u2019 drug continues to surprise and exceed expectations","volume":"70","author":"Crump","year":"2017","journal-title":"J. Antibiot. (Tokyo)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1038\/371707a0","article-title":"Cloning of an avermectin-sensitive glutamate-gated chloride channel from caenorhabditis elegans","volume":"371","author":"Cully","year":"1994","journal-title":"Nature"},{"key":"B13","first-page":"353","article-title":"Ivermectin efficacy against triatoma infestans in vivo using hen model","volume":"2","author":"Dad\u00e9","year":"2014","journal-title":"J. Pharm. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"324","DOI":"10.7705\/biomedica.v34i2.3316","article-title":"Evaluation of the toxic effects of doramectin, ivermectin and eprinomectin against triatoma infestans using a rat model","volume":"37","author":"Dad\u00e9","year":"2017","journal-title":"Biom\u00e9dica"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e00085","DOI":"10.1128\/AAC.00085-19","article-title":"Ivermectin impairs the development of sexual and asexual stages of plasmodium falciparum In vitro","volume":"63","author":"de Carvalho","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"B16","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.synbio.2018.12.003","article-title":"Streptomyces avermitilis industrial strain as cell factory for ivermectin B1a production","volume":"4","author":"Deng","year":"2019","journal-title":"Synth. Syst. Biotechnol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e1355","DOI":"10.1542\/peds.2015-0746","article-title":"Head lice","volume":"135","author":"Devore","year":"2015","journal-title":"Pediatrics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1016\/j.bbrc.2018.07.115","article-title":"Molecular basis for the lack of auto-inhibition of plasmodium falciparum importin \u03b1","volume":"503","author":"Dey","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1590\/s0074-02762005000800002","article-title":"Ticks, ivermectin, and experimental chagas disease","volume":"100","author":"Dias","year":"2005","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2866","DOI":"10.1093\/bioinformatics\/btw230","article-title":"Combenefit: an interactive platform for the analysis and visualization of drug combinations","volume":"32","author":"Di Veroli","year":"2016","journal-title":"Bioinform. Oxf. Engl."},{"key":"B21","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1159\/000237908","article-title":"Trypanostatic drug action: its relation to relapse following chemotherapy","volume":"26","author":"Ercoli","year":"1980","journal-title":"Chemotherapy"},{"key":"B22","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nrmicro.2016.193","article-title":"Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need","volume":"15","author":"Field","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1080\/01459740.2017.1360878","article-title":"From lemongrass to ivermectin: Ethnomedical management of chagas disease in tropical Bolivia","volume":"37","author":"Forsyth","year":"2018","journal-title":"Med. Anthropol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1146\/annurev.biochem.67.1.153","article-title":"RIBONUCLEASE p: Unity and diversity in a tRNA processing ribozyme","volume":"67","author":"Frank","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1211\/146080800128735764","article-title":"Potentiation of doxorubicin-induced apoptosis of resistant mouse leukaemia cells by ivermectin","volume":"6","author":"Furusawa","year":"2000","journal-title":"Pharm. Pharmacol. Commun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"665\u2013674","DOI":"10.1007\/s00044-020-02512-9","article-title":"In vitro and in silico evaluations of new aryloxy-1,4-naphthoquinones as anti-trypanosoma cruzi agents","volume":"29","author":"Gonz\u00e1lez","year":"2020","journal-title":"Medicinal Chemistry Research"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1177\/009127002401382731","article-title":"Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects","volume":"42","author":"Guzzo","year":"2002","journal-title":"J. Clin. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e0151934","DOI":"10.1371\/journal.pone.0151934","article-title":"Evolution of pentameric ligand-gated ion channels: Pro-loop receptors","volume":"11","author":"Jaiteh","year":"2016","journal-title":"PloS One"},{"key":"B29","first-page":", 175-180","article-title":"Comparison between the efficacy of ivermectin and other drugs in treatment of cutaneous leishmaniasis","volume":"23","author":"Kadir","year":"2009","journal-title":"Iraqi J. Vet. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/nrd4683","article-title":"Hit and lead criteria in drug discovery for infectious diseases of the developing world","volume":"14","author":"Katsuno","year":"2015","journal-title":"Nat. Rev. Drug Discovery"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e5549","DOI":"10.1371\/journal.pone.0055497","article-title":"Trypanosoma cruzi response to sterol biosynthesis inhibitors: Morphophysiological alterations leading to cell death","volume":"8","author":"Kessler","year":"2013","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.pt.2017.02.004","article-title":"Ivermectin - old drug, new tricks","volume":"33","author":"Laing","year":"2017","journal-title":"Trends Parasitol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.molbiopara.2018.12.006","article-title":"Protean permeases: Diverse roles for membrane transport proteins in kinetoplastid protozoa","volume":"227","author":"Landfear","year":"2019","journal-title":"Mol. Biochem. Parasitol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.ejps.2006.10.004","article-title":"Interaction of macrocyclic lactones with p-glycoprotein: Structure\u2013affinity relationship","volume":"30","author":"Lespine","year":"2007","journal-title":"Eur. J. Pharm. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"D458","DOI":"10.1093\/nar\/gkaa937","article-title":"SMART: recent updates, new developments and status in 2020","volume":"49","author":"Letunic","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B36","first-page":"448","article-title":"In vitro susceptibility of trypanosoma cruzi strains from santander, Colombia, to hexadecylphosphocholine (miltefosine), nifurtimox and benznidazole","volume":"29","author":"Luna","year":"2009","journal-title":"Biomed. Rev. Inst. Nac. Salud"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2019.118566","article-title":"Evidence of nuclear transport mechanisms in the protozoan parasite giardia lamblia","volume":"1867","author":"Mayol","year":"2020","journal-title":"Biochim. Biophys. Acta BBA Mol. Cell Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e02005","DOI":"10.1128\/AAC.02005-16","article-title":"Inhibition of plasmodium liver infection by ivermectin","volume":"61","author":"Mendes","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"B39","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.bcp.2011.10.010","article-title":"Ivermectin induces p-glycoprotein expression and function through mRNA stabilization in murine hepatocyte cell line","volume":"83","author":"M\u00e9nez","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"D412","DOI":"10.1093\/nar\/gkaa913","article-title":"Pfam: The protein families database in 2021","volume":"49","author":"Mistry","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1111\/cbdd.13332","article-title":"Trypanosoma cruzi biochemical changes and cell death induced by an organometallic platinum-based compound","volume":"92","author":"Mosquillo","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e0232171","DOI":"10.1371\/journal.pone.0232171","article-title":"Effects of combined drug treatments on plasmodium falciparum: In vitro assays with doxycycline, ivermectin and efflux pump inhibitors","volume":"15","author":"Nodari","year":"2020","journal-title":"PloS One"},{"key":"B43","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.jacc.2013.05.046","article-title":"Council on chagas disease of the interamerican society of cardiology 2013. chagas disease: an overview of clinical and epidemiological aspects","volume":"62","author":"Nunes","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"186\u2013188","DOI":"10.3923\/jms.2005.186.188","article-title":"Cutaneous leishmaniasis: A report of its treatment with mectizan in sokoto, Nigeria","volume":"5","author":"Opara","year":"2005","journal-title":"J. Med. Sci"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.521","article-title":"Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP","volume":"5","author":"Panchal","year":"2014","journal-title":"Cell Death Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/S0140-6736(17)31612-4","article-title":"Chagas disease","volume":"391","author":"P\u00e9rez-Molina","year":"2018","journal-title":"Lancet"},{"key":"B47","doi-asserted-by":"publisher","first-page":"325","DOI":"10.4161\/chan.5.4.16822","article-title":"Identifying bacterial and archaeal homologs of pentameric ligand-gated ion channel (pLGIC) family using domain-based and alignment-based approaches","volume":"5","author":"Rendon","year":"2011","journal-title":"Channels Austin Tex"},{"key":"B48","doi-asserted-by":"publisher","first-page":"23\u201332","DOI":"10.1016\/j.exppara.2016.10.007","article-title":"Pentamidine antagonizes the benznidazole\u2019s effect in vitro, and lacks of synergy in vivo: Implications about the polyamine transport as an anti-trypanosoma cruzi target","volume":"171","author":"Seguel","year":"2016","journal-title":"Experiment. Parasitol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.wem.2013.09.008","article-title":"The use of ivermectin to kill ixodes scapularis ticks feeding on humans","volume":"25","author":"Sheele","year":"2014","journal-title":"Wilderness Environ. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1007\/978-1-4939-7154-1_30","article-title":"Informatics approaches for predicting, understanding, and testing cancer drug combinations","volume":"1636","author":"Tang","year":"2017","journal-title":"Methods Mol. Biol. Clifton NJ"},{"key":"B51","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1186\/s12879-015-0983-z","article-title":"Scabies: an ancient global disease with a need for new therapies","volume":"15","author":"Thomas","year":"2015","journal-title":"BMC Infect. Dis."},{"key":"B52","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/978-1-4612-3626-9_5","volume-title":"Mode of action of ivermectin BT - ivermectin and abamectin","author":"Turner","year":"1989"},{"key":"B53","doi-asserted-by":"crossref","first-page":"143","DOI":"10.4103\/0972-9062.213454","article-title":"Effect of ivermectin on trypanosoma brucei brucei in experimentally infected mice","volume":"49","author":"Udensi","year":"2012","journal-title":"J. Vector Borne Dis."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001618","article-title":"Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against trypanosoma brucei","volume":"6","author":"Vincent","year":"2012","journal-title":"PloS Negl. Trop. Dis."},{"key":"B55","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1042\/BJ20120150","article-title":"Ivermectin is a specific inhibitor of importin \u03b1\/\u03b2-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus","volume":"443","author":"Wagstaff","year":"2012","journal-title":"Biochem. J."},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.663586","article-title":"Repurposing ivermectin for COVID-19: Molecular aspects and therapeutic possibilities","volume":"12","author":"Wehbe","year":"2021","journal-title":"Front. Immunol."},{"key":"B57","first-page":"33","article-title":"Chagas disease in Latin America : an epidemiological update based on 2010 estimates","volume":"90","year":"2015","journal-title":"Wkly. Epidemiol. Rec."},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104760","article-title":"The broad spectrum antiviral ivermectin targets the host nuclear transport importin \u03b1\/\u03b21 heterodimer","volume":"177","author":"Yang","year":"2020","journal-title":"Antiviral Res."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.885268\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T01:57:11Z","timestamp":1727661431000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.885268\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,28]]},"references-count":58,"alternative-id":["10.3389\/fcimb.2022.885268"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.885268","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,28]]},"article-number":"885268"}}