Show simple item record

dc.contributor.authorCampos, Mônica C.
dc.contributor.authorPhelan, Jody
dc.contributor.authorFrancisco, Amanda F.
dc.contributor.authorTaylor, Martin C.
dc.contributor.authorLewis, Michael D.
dc.contributor.authorPain, Arnab
dc.contributor.authorClark, Taane G.
dc.contributor.authorKelly, John M.
dc.date.accessioned2017-11-02T09:09:33Z
dc.date.available2017-11-02T09:09:33Z
dc.date.issued2017-10-25
dc.identifier.citationCampos MC, Phelan J, Francisco AF, Taylor MC, Lewis MD, et al. (2017) Genome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole. Scientific Reports 7. Available: http://dx.doi.org/10.1038/s41598-017-14986-6.
dc.identifier.issn2045-2322
dc.identifier.pmid29089615
dc.identifier.doi10.1038/s41598-017-14986-6
dc.identifier.urihttp://hdl.handle.net/10754/626094
dc.description.abstractChagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 5–8 million people in Latin America. Although the nitroheterocyclic compound benznidazole has been the front-line drug for several decades, treatment failures are common. Benznidazole is a pro-drug and is bio-activated within the parasite by the mitochondrial nitroreductase TcNTR-1, leading to the generation of reactive metabolites that have trypanocidal activity. To better assess drug action and resistance, we sequenced the genomes of T. cruzi Y strain (35.5 Mb) and three benznidazole-resistant clones derived from a single drug-selected population. This revealed the genome-wide accumulation of mutations in the resistant parasites, in addition to variations in DNA copy-number. We observed mutations in DNA repair genes, linked with increased susceptibility to DNA alkylating and inter-strand cross-linking agents. Stop-codon-generating mutations in TcNTR-1 were associated with cross-resistance to other nitroheterocyclic drugs. Unexpectedly, the clones were also highly resistant to the ergosterol biosynthesis inhibitor posaconazole, a drug proposed for use against T. cruzi infections, in combination with benznidazole. Our findings therefore identify the highly mutagenic activity of benznidazole metabolites in T. cruzi, demonstrate that this can result in multi-drug resistance, and indicate that vigilance will be required if benznidazole is used in combination therapy.
dc.description.sponsorshipM.C.C. was funded by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. J.M.K. acknowledges financial support from the British Heart Foundation (Grant PG/13/88/30556) and the Drugs for Neglected Diseases initiative (DNDi). M.D.L. is supported by an EU Marie Curie Fellowship. J.P. is funded by a UK BBSRC LiDO PhD studentship. T.G.C. is funded by the UK MRC (Grant no. MR/K000551/1, MR/M01360X/1, MR/N010469/1). The authors would like to thank members of KAUST Bioscience Core Sequencing facility for sequencing the parasites. This part of the work was funded by Faculty baseline funding (BAS/1/1020–01–01) to A.P. We thank Arkady Mustaev (New Jersey Medical School –Rutgers) for kindly providing BODIPY conjugated posaconazole,
dc.publisherSpringer Nature
dc.relation.urlhttps://www.nature.com/articles/s41598-017-14986-6
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleGenome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentPathogen Genomics Laboratory
dc.identifier.journalScientific Reports
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionDepartment of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
dc.contributor.institutionDepartment of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
kaust.personPain, Arnab
kaust.grant.numberBAS/1/1020–01–01
refterms.dateFOA2018-06-13T13:20:01Z


Files in this item

Thumbnail
Name:
s41598-017-14986-6.pdf
Size:
1.688Mb
Format:
PDF
Description:
Main article
Thumbnail
Name:
41598_2017_14986_MOESM1_ESM.pdf
Size:
305.1Kb
Format:
PDF
Description:
Supplemental files

This item appears in the following Collection(s)

Show simple item record

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.