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Open AccessArticle

Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates

1
Programa de Pós-graduação em Modelagem Computacional, Universidade Federal de Juiz de Fora–UFJF, Juiz de Fora 36036-330, Brazil
2
Fiocruz, Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Av. Brasil 4365, Rio de Janeiro 21040-360, Brazil
3
Laboratório de Modelagem Molecular e Planejamento de Fármacos, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
4
Fiocruz, Programa de Computação Científica, Av. Brasil 4365, Rio de Janeiro 21040-360, Brazil
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Catalysts 2020, 10(5), 543; https://doi.org/10.3390/catal10050543
Received: 31 December 2019 / Revised: 10 February 2020 / Accepted: 16 February 2020 / Published: 14 May 2020
(This article belongs to the Special Issue Flavin Monooxygenases)
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. View Full-Text
Keywords: EthA; ethionamide resistance; BVMO; molecular dynamics; thermodynamic integration EthA; ethionamide resistance; BVMO; molecular dynamics; thermodynamic integration
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de Souza, V.C.; Antunes, D.; Santos, L.H.; Goliatt, P.V.Z.C.; Caffarena, E.R.; Guimarães, A.C.R.; Galvão, T.C. 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 2020, 10, 543.

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