Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2020 |
| Outros Autores: | , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/42455 |
Resumo: | Universidade Federal de Juiz de Fora. Programa de Pós-graduação em Modelagem Computacional. Juiz de Fpra, MG, Brasil. |
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Souza, Vinicius Carius deAntunes, DeborahSantos, Lucianna H. S.Goliatt, Priscila Vanessa Zabala CaprilesCaffarena, Ernesto RaulGuimarães, Ana Carolina RamosGalvão, Teca Calcagno2020-07-29T20:27:46Z2020-07-29T20:27:46Z2020SOUZA. Vinicius Carlos de et al. Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates. Catalysts, v. 10, n. 543, 15p, 2020.2073-4344https://www.arca.fiocruz.br/handle/icict/4245510.20944/preprints202003.0470.v12073-4344engMDPIEthionamideResistência à ethionamidaDinâmica molecularIntegração termodinâmicaEthAEthionamide resistanceBVMOMolecular dynamicsThermodynamic integrationInsights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolatesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversidade Federal de Juiz de Fora. Programa de Pós-graduação em Modelagem Computacional. Juiz de Fpra, MG, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática, Rio de Janeiro, RJ, Brasil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Modelagem Molecular e Planejamento de Fármacos. Belo Horizonte, MG, Brasil.Universidade Federal de Juiz de Fora. Programa de Pós-graduação em Modelagem Computacional. Juiz de Fpra, MG, Brasil.Fundação Oswaldo Cruz. Programa de Computação Científica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática, Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática, Rio de Janeiro, RJ, Brasil.Mutation in the ethionamide (ETH) activating enzyme, EthA, is the main factor determining resistance to this drug, used to treat TB patients infected with MDR and XDR Mycobacterium tuberculosis isolates. Many mutations in EthA of ETH resistant (ETH-R) isolates have been described but their roles in resistance remain uncharacterized, partly because structural studies on the enzyme are lacking. Thus, we took a two-tier approach to evaluate two mutations (Y50C and T453I) found in ETH-R clinical isolates. First, we used a combination of comparative modeling, molecular docking, and molecular dynamics to build an EthA model in complex with ETH that has hallmark features of structurally characterized homologs. Second, we used free energy computational calculations for the reliable prediction of relative free energies between the wild type and mutant enzymes. The ΔΔG values for Y50C and T453I mutant enzymes in complex with FADH2-NADP-ETH were 3.34 (+/−0.55) and 8.11 (+/−0.51) kcal/mol, respectively, compared to the wild type complex. The positive ΔΔG values indicate that the wild type complex is more stable than the mutants, with the T453I complex being the least stable. These are the first results shedding light on the molecular basis of ETH resistance, namely reduced complex stability of mutant EthA.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/42455/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALDeboraCAntunes_TecaCGalvao_etal_IOC_2020.pdfDeboraCAntunes_TecaCGalvao_etal_IOC_2020.pdfapplication/pdf1993986https://www.arca.fiocruz.br/bitstream/icict/42455/2/DeboraCAntunes_TecaCGalvao_etal_IOC_2020.pdf7b6603c4f4a0fd1b0950bb2cccfd8dacMD52TEXTDeboraCAntunes_TecaCGalvao_etal_IOC_2020.pdf.txtDeboraCAntunes_TecaCGalvao_etal_IOC_2020.pdf.txtExtracted texttext/plain47071https://www.arca.fiocruz.br/bitstream/icict/42455/3/DeboraCAntunes_TecaCGalvao_etal_IOC_2020.pdf.txtd1e60f359cde4ccc298a8718fbe677b0MD53icict/424552021-11-10 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| dc.title.pt_BR.fl_str_mv |
Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates |
| title |
Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates |
| spellingShingle |
Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates Souza, Vinicius Carius de Ethionamide Resistência à ethionamida Dinâmica molecular Integração termodinâmica EthA Ethionamide resistance BVMO Molecular dynamics Thermodynamic integration |
| title_short |
Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates |
| title_full |
Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates |
| title_fullStr |
Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates |
| title_full_unstemmed |
Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates |
| title_sort |
Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates |
| author |
Souza, Vinicius Carius de |
| author_facet |
Souza, Vinicius Carius de Antunes, Deborah Santos, Lucianna H. S. Goliatt, Priscila Vanessa Zabala Capriles Caffarena, Ernesto Raul Guimarães, Ana Carolina Ramos Galvão, Teca Calcagno |
| author_role |
author |
| author2 |
Antunes, Deborah Santos, Lucianna H. S. Goliatt, Priscila Vanessa Zabala Capriles Caffarena, Ernesto Raul Guimarães, Ana Carolina Ramos Galvão, Teca Calcagno |
| author2_role |
author author author author author author |
| dc.contributor.author.fl_str_mv |
Souza, Vinicius Carius de Antunes, Deborah Santos, Lucianna H. S. Goliatt, Priscila Vanessa Zabala Capriles Caffarena, Ernesto Raul Guimarães, Ana Carolina Ramos Galvão, Teca Calcagno |
| dc.subject.other.pt_BR.fl_str_mv |
Ethionamide Resistência à ethionamida Dinâmica molecular Integração termodinâmica |
| topic |
Ethionamide Resistência à ethionamida Dinâmica molecular Integração termodinâmica EthA Ethionamide resistance BVMO Molecular dynamics Thermodynamic integration |
| dc.subject.en.pt_BR.fl_str_mv |
EthA Ethionamide resistance BVMO Molecular dynamics Thermodynamic integration |
| description |
Universidade Federal de Juiz de Fora. Programa de Pós-graduação em Modelagem Computacional. Juiz de Fpra, MG, Brasil. |
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2020 |
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2020-07-29T20:27:46Z |
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2020-07-29T20:27:46Z |
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2020 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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SOUZA. Vinicius Carlos de et al. Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates. Catalysts, v. 10, n. 543, 15p, 2020. |
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https://www.arca.fiocruz.br/handle/icict/42455 |
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2073-4344 |
| dc.identifier.doi.none.fl_str_mv |
10.20944/preprints202003.0470.v1 |
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2073-4344 |
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SOUZA. Vinicius Carlos de et al. Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates. Catalysts, v. 10, n. 543, 15p, 2020. 2073-4344 10.20944/preprints202003.0470.v1 |
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