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

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 XDRMycobacterium tuberculosisisolates. Many mutations in EthA of ETH resistant (ETH-R) isolates have been described but their roles in re...

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Veröffentlicht in:Catalysts 2020-05, Vol.10 (5), p.543, Article 543
Hauptverfasser: de Souza, Vinicius Carius, Antunes, Deborah, Santos, Lucianna H. S., Zabala Capriles Goliatt, Priscila Vanessa, Caffarena, Ernesto Raul, Ramos Guimaraes, Ana Carolina, Galvao, Teca Calcagno
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container_title Catalysts
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creator de Souza, Vinicius Carius
Antunes, Deborah
Santos, Lucianna H. S.
Zabala Capriles Goliatt, Priscila Vanessa
Caffarena, Ernesto Raul
Ramos Guimaraes, Ana Carolina
Galvao, Teca Calcagno
description 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 XDRMycobacterium tuberculosisisolates. 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 Delta Delta G values for Y50C and T453I mutant enzymes in complex with FADH(2)-NADP-ETH were 3.34 (+/-0.55) and 8.11 (+/-0.51) kcal/mol, respectively, compared to the wild type complex. The positive Delta Delta G 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.
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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 Delta Delta G values for Y50C and T453I mutant enzymes in complex with FADH(2)-NADP-ETH were 3.34 (+/-0.55) and 8.11 (+/-0.51) kcal/mol, respectively, compared to the wild type complex. The positive Delta Delta G values indicate that the wild type complex is more stable than the mutants, with the T453I complex being the least stable. 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subjects Amino acids
Binding sites
BVMO
Catalysis
Catalysts
Chemical reactions
Chemistry
Chemistry, Physical
Drug resistance
Enzymes
EthA
ethionamide resistance
Free energy
Homology
Ligands
Molecular docking
Molecular dynamics
Mutation
Physical Sciences
Resistance factors
Science & Technology
Simulation
thermodynamic integration
Tuberculosis
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
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