Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan

Detalhes bibliográficos
Autor(a) principal: Rosa-Teijeiro, Chloé
Data de Publicação: 2021
Outros Autores: Wagner, Victoria, Corbei, Audrey, d'Annessa, Ilda, Leprohon, Philippe, Monte Neto, Rubens Lima do, Fernandez-Prada, Christopher
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/51942
Resumo: Département de Pathologie et Microbiologie. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada/The Research Group on Infectious Diseases in Production Animals. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada
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spelling Rosa-Teijeiro, ChloéWagner, VictoriaCorbei, Audreyd'Annessa, IldaLeprohon, PhilippeMonte Neto, Rubens Lima doFernandez-Prada, Christopher2022-03-31T13:36:27Z2022-03-31T13:36:27Z2021ROSA-TEIJEIRO, Chloé et al. Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan. Parasites & vectors, v. 14, n. 1, p. 438,2021. /doi.org/10.1186/s13071-021-04947-41756-3305https://www.arca.fiocruz.br/handle/icict/5194210.1186/s13071-021-04947-4engBioMed CentralThree different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecaninfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleDépartement de Pathologie et Microbiologie. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada/The Research Group on Infectious Diseases in Production Animals. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, CanadaDépartement de Pathologie et Microbiologie. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada/The Research Group on Infectious Diseases in Production Animals. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, CanadaDépartement de Pathologie et Microbiologie. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada/The Research Group on Infectious Diseases in Production Animals. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, CanadaMedtronic EMEA. Study and Scientific Solutions. Milan, Italy.Centre de Recherche en Infectiologie du Centre de Recherche du Centre Hospitalier Universitaire de Québec. Université Laval. Quebec City, CanadaFundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, BrazilDépartement de Pathologie et Microbiologie. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada/The Research Group on Infectious Diseases in Production Animals. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada/Department of Microbiology and Immunology. Faculty of Medicine. McGill University. Montréal, QC, CanadaBackground: The evolution of drug resistance is one of the biggest challenges in leishmaniasis and has prompted the need for new antileishmanial drugs. Repurposing of approved drugs is a faster and very attractive strategy that is gaining supporters worldwide. Different anticancer topoisomerase 1B (TOP1B) inhibitors have shown strong antileishmanial activity and promising selective indices, supporting the potential repurposing of these drugs. However, cancer cells and Leishmania share the ability to become rapidly resistant. The aim of this study was to complete a whole-genome exploration of the effects caused by exposure to topotecan in order to highlight the potential mechanisms deployed by Leishmania to favor its survival in the presence of a TOP1B inhibitor. Methods: We used a combination of stepwise drug resistance selection, whole-genome sequencing, functional validation, and theoretical approaches to explore the propensity of and potential mechanisms deployed by three independent clones of L. infantum to resist the action of TOP1B inhibitor topotecan. Results: We demonstrated that L. infantum is capable of becoming resistant to high concentrations of topotecan without impaired growth ability. No gene deletions or amplifications were identified from the next-generation sequencing data in any of the three resistant lines, ruling out the overexpression of efflux pumps as the preferred mechanism of topotecan resistance. We identified three different mutations in the large subunit of the leishmanial TOP1B (Top1B F187Y , Top1B G191A , and Top1B W232R ). Overexpression of these mutated alleles in the wild-type background led to high levels of resistance to topotecan. Computational molecular dynamics simulations, in both covalent and non-covalent complexes, showed that these mutations have an effect on the arrangement of the catalytic pentad and on the interaction of these residues with surrounding amino acids and DNA. This altered architecture of the binding pocket results in decreased persistence of topotecan in the ternary complex. Conclusions: This work helps elucidate the previously unclear potential mechanisms of topotecan resistance in Leishmania by mutations in the large subunit of TOP1B and provides a valuable clue for the design of improved inhibitors to combat resistance in both leishmaniasis and cancer. Our data highlights the importance of including drug resistance evaluation in drug discovery cascades.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-83082https://www.arca.fiocruz.br/bitstream/icict/51942/1/license.txt9193a7c197bc67acd023525e72a03240MD51ORIGINALThree different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan.pdfThree different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan.pdfapplication/pdf4843975https://www.arca.fiocruz.br/bitstream/icict/51942/2/Three%20different%20mutations%20in%20the%20DNA%20topoisomerase%201B%20in%20Leishmania%20infantum%20contribute%20to%20resistance%20to%20antitumor%20drug%20topotecan.pdf43c2adb7ba0df8a64d14ee4b82a45bd6MD52icict/519422022-03-31 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dc.title.pt_BR.fl_str_mv Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
title Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
spellingShingle Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
Rosa-Teijeiro, Chloé
title_short Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
title_full Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
title_fullStr Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
title_full_unstemmed Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
title_sort Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
author Rosa-Teijeiro, Chloé
author_facet Rosa-Teijeiro, Chloé
Wagner, Victoria
Corbei, Audrey
d'Annessa, Ilda
Leprohon, Philippe
Monte Neto, Rubens Lima do
Fernandez-Prada, Christopher
author_role author
author2 Wagner, Victoria
Corbei, Audrey
d'Annessa, Ilda
Leprohon, Philippe
Monte Neto, Rubens Lima do
Fernandez-Prada, Christopher
author2_role author
author
author
author
author
author
dc.contributor.author.fl_str_mv Rosa-Teijeiro, Chloé
Wagner, Victoria
Corbei, Audrey
d'Annessa, Ilda
Leprohon, Philippe
Monte Neto, Rubens Lima do
Fernandez-Prada, Christopher
description Département de Pathologie et Microbiologie. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada/The Research Group on Infectious Diseases in Production Animals. Faculté de Médecine Vétérinaire. Université de Montréal. Saint-Hyacinthe, QC, Canada
publishDate 2021
dc.date.issued.fl_str_mv 2021
dc.date.accessioned.fl_str_mv 2022-03-31T13:36:27Z
dc.date.available.fl_str_mv 2022-03-31T13:36:27Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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status_str publishedVersion
dc.identifier.citation.fl_str_mv ROSA-TEIJEIRO, Chloé et al. Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan. Parasites & vectors, v. 14, n. 1, p. 438,2021. /doi.org/10.1186/s13071-021-04947-4
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/51942
dc.identifier.issn.pt_BR.fl_str_mv 1756-3305
dc.identifier.doi.none.fl_str_mv 10.1186/s13071-021-04947-4
identifier_str_mv ROSA-TEIJEIRO, Chloé et al. Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan. Parasites & vectors, v. 14, n. 1, p. 438,2021. /doi.org/10.1186/s13071-021-04947-4
1756-3305
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dc.language.iso.fl_str_mv eng
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dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
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