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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| 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. |
| doi_str_mv | 10.3390/catal10050543 |
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S. ; Zabala Capriles Goliatt, Priscila Vanessa ; Caffarena, Ernesto Raul ; Ramos Guimaraes, Ana Carolina ; Galvao, Teca Calcagno</creator><creatorcontrib>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</creatorcontrib><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.</description><identifier>ISSN: 2073-4344</identifier><identifier>EISSN: 2073-4344</identifier><identifier>DOI: 10.3390/catal10050543</identifier><language>eng</language><publisher>BASEL: Mdpi</publisher><subject>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</subject><ispartof>Catalysts, 2020-05, Vol.10 (5), p.543, Article 543</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). 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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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S.</au><au>Zabala Capriles Goliatt, Priscila Vanessa</au><au>Caffarena, Ernesto Raul</au><au>Ramos Guimaraes, Ana Carolina</au><au>Galvao, Teca Calcagno</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates</atitle><jtitle>Catalysts</jtitle><stitle>CATALYSTS</stitle><date>2020-05-01</date><risdate>2020</risdate><volume>10</volume><issue>5</issue><spage>543</spage><pages>543-</pages><artnum>543</artnum><issn>2073-4344</issn><eissn>2073-4344</eissn><abstract>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.</abstract><cop>BASEL</cop><pub>Mdpi</pub><doi>10.3390/catal10050543</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-0031-6537</orcidid><orcidid>https://orcid.org/0000-0002-8353-3034</orcidid><orcidid>https://orcid.org/0000-0002-6910-0697</orcidid><orcidid>https://orcid.org/0000-0002-2927-0800</orcidid><orcidid>https://orcid.org/0000-0001-8075-3253</orcidid><orcidid>https://orcid.org/0000-0003-1260-543X</orcidid><oa>free_for_read</oa></addata></record> |
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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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