A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs I...

Autores
Franceschelli, Jorgelina Judith; Belardinelli, Juan Manuel; Tong, Ping; Loftus, Brendan; Recio Balsells, Alejandro Iván; Labadie, Guillermo Roberto; Gordon, Stephen V.; Morbidoni, Héctor Ricardo
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Clinical isolates of Mycobacterium tuberculosis and Mycobacterium bovis are differentially susceptible to 2-Thiophen Hydrazide (TCH); however its mechanism of action or the reasons for that difference are unknown. We report herein that under our experimental conditions, TCH inhibits M. tuberculosis in solid but not in liquid medium, and that in spite of resembling Isoniazid and Ethionamide, it does not affect mycolic acid synthesis. To understand the mechanisms of action of TCH we isolated M. tuberculosis TCH resistant mutants which fell into two groups; one resistant to TCH and Isoniazid but not to Ethionamide or Triclosan, and the other resistant only to TCH with no, or marginal, cross resistance to Isoniazid. A S315T katG mutation conferred resistance to TCH while katG expression from a plasmid reduced M. tuberculosis MIC to this drug, suggesting a possible involvement of KatG in TCH activation. Whole genome sequencing of mutants from this second group revealed a single mutation in the alkylhydroperoxide reductase ahpC promoter locus in half of the mutants, while the remaining contained mutations in dispensable genes. This is the first report of the genetics underlying the action of TCH and of the involvement of ahpC as the sole basis for resistance to an anti-tubercular compound.
Fil: Franceschelli, Jorgelina Judith. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
Fil: Belardinelli, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. State University of Colorado - Fort Collins; Estados Unidos
Fil: Tong, Ping. University College Dublin; Irlanda. University of Edinburgh; Reino Unido
Fil: Loftus, Brendan. University College Dublin; Irlanda
Fil: Recio Balsells, Alejandro Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina
Fil: Labadie, Guillermo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina
Fil: Gordon, Stephen V.. University College Dublin; Irlanda
Fil: Morbidoni, Héctor Ricardo. Universidad Nacional de Rosario; Argentina
Materia
2-THIOPHEN CARBOXYLIC ACID HYDRAZIDE
ALKYLHYDROPEROXIDASE
MYCOBACTERIUM BOVIS
MYCOBACTERIUM TUBERCULOSIS
NON TUBERCULOUS MYCOBACTERIA
TCH RESISTANT MUTANTS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/91966
Acceder
id CONICETDig_6eb28c271a18b0172e27a066111f5152
oai_identifier_str oai:ri.conicet.gov.ar:11336/91966
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and EthionamideFranceschelli, Jorgelina JudithBelardinelli, Juan ManuelTong, PingLoftus, BrendanRecio Balsells, Alejandro IvánLabadie, Guillermo RobertoGordon, Stephen V.Morbidoni, Héctor Ricardo2-THIOPHEN CARBOXYLIC ACID HYDRAZIDEALKYLHYDROPEROXIDASEMYCOBACTERIUM BOVISMYCOBACTERIUM TUBERCULOSISNON TUBERCULOUS MYCOBACTERIATCH RESISTANT MUTANTShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Clinical isolates of Mycobacterium tuberculosis and Mycobacterium bovis are differentially susceptible to 2-Thiophen Hydrazide (TCH); however its mechanism of action or the reasons for that difference are unknown. We report herein that under our experimental conditions, TCH inhibits M. tuberculosis in solid but not in liquid medium, and that in spite of resembling Isoniazid and Ethionamide, it does not affect mycolic acid synthesis. To understand the mechanisms of action of TCH we isolated M. tuberculosis TCH resistant mutants which fell into two groups; one resistant to TCH and Isoniazid but not to Ethionamide or Triclosan, and the other resistant only to TCH with no, or marginal, cross resistance to Isoniazid. A S315T katG mutation conferred resistance to TCH while katG expression from a plasmid reduced M. tuberculosis MIC to this drug, suggesting a possible involvement of KatG in TCH activation. Whole genome sequencing of mutants from this second group revealed a single mutation in the alkylhydroperoxide reductase ahpC promoter locus in half of the mutants, while the remaining contained mutations in dispensable genes. This is the first report of the genetics underlying the action of TCH and of the involvement of ahpC as the sole basis for resistance to an anti-tubercular compound.Fil: Franceschelli, Jorgelina Judith. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Belardinelli, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. State University of Colorado - Fort Collins; Estados UnidosFil: Tong, Ping. University College Dublin; Irlanda. University of Edinburgh; Reino UnidoFil: Loftus, Brendan. University College Dublin; IrlandaFil: Recio Balsells, Alejandro Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Labadie, Guillermo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Gordon, Stephen V.. University College Dublin; IrlandaFil: Morbidoni, Héctor Ricardo. Universidad Nacional de Rosario; ArgentinaChurchill Livingstone2018-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/91966Franceschelli, Jorgelina Judith; Belardinelli, Juan Manuel; Tong, Ping; Loftus, Brendan; Recio Balsells, Alejandro Iván; et al.; A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide; Churchill Livingstone; Tuberculosis (Edinb); 112; 9-2018; 69-781472-9792CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.tube.2018.08.001info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S1472979218301598info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:20:57Zoai:ri.conicet.gov.ar:11336/91966instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:20:57.747CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide
title A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide
spellingShingle A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide
Franceschelli, Jorgelina Judith
2-THIOPHEN CARBOXYLIC ACID HYDRAZIDE
ALKYLHYDROPEROXIDASE
MYCOBACTERIUM BOVIS
MYCOBACTERIUM TUBERCULOSIS
NON TUBERCULOUS MYCOBACTERIA
TCH RESISTANT MUTANTS
title_short A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide
title_full A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide
title_fullStr A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide
title_full_unstemmed A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide
title_sort A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide
dc.creator.none.fl_str_mv Franceschelli, Jorgelina Judith
Belardinelli, Juan Manuel
Tong, Ping
Loftus, Brendan
Recio Balsells, Alejandro Iván
Labadie, Guillermo Roberto
Gordon, Stephen V.
Morbidoni, Héctor Ricardo
author Franceschelli, Jorgelina Judith
author_facet Franceschelli, Jorgelina Judith
Belardinelli, Juan Manuel
Tong, Ping
Loftus, Brendan
Recio Balsells, Alejandro Iván
Labadie, Guillermo Roberto
Gordon, Stephen V.
Morbidoni, Héctor Ricardo
author_role author
author2 Belardinelli, Juan Manuel
Tong, Ping
Loftus, Brendan
Recio Balsells, Alejandro Iván
Labadie, Guillermo Roberto
Gordon, Stephen V.
Morbidoni, Héctor Ricardo
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv 2-THIOPHEN CARBOXYLIC ACID HYDRAZIDE
ALKYLHYDROPEROXIDASE
MYCOBACTERIUM BOVIS
MYCOBACTERIUM TUBERCULOSIS
NON TUBERCULOUS MYCOBACTERIA
TCH RESISTANT MUTANTS
topic 2-THIOPHEN CARBOXYLIC ACID HYDRAZIDE
ALKYLHYDROPEROXIDASE
MYCOBACTERIUM BOVIS
MYCOBACTERIUM TUBERCULOSIS
NON TUBERCULOUS MYCOBACTERIA
TCH RESISTANT MUTANTS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Clinical isolates of Mycobacterium tuberculosis and Mycobacterium bovis are differentially susceptible to 2-Thiophen Hydrazide (TCH); however its mechanism of action or the reasons for that difference are unknown. We report herein that under our experimental conditions, TCH inhibits M. tuberculosis in solid but not in liquid medium, and that in spite of resembling Isoniazid and Ethionamide, it does not affect mycolic acid synthesis. To understand the mechanisms of action of TCH we isolated M. tuberculosis TCH resistant mutants which fell into two groups; one resistant to TCH and Isoniazid but not to Ethionamide or Triclosan, and the other resistant only to TCH with no, or marginal, cross resistance to Isoniazid. A S315T katG mutation conferred resistance to TCH while katG expression from a plasmid reduced M. tuberculosis MIC to this drug, suggesting a possible involvement of KatG in TCH activation. Whole genome sequencing of mutants from this second group revealed a single mutation in the alkylhydroperoxide reductase ahpC promoter locus in half of the mutants, while the remaining contained mutations in dispensable genes. This is the first report of the genetics underlying the action of TCH and of the involvement of ahpC as the sole basis for resistance to an anti-tubercular compound.
Fil: Franceschelli, Jorgelina Judith. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
Fil: Belardinelli, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. State University of Colorado - Fort Collins; Estados Unidos
Fil: Tong, Ping. University College Dublin; Irlanda. University of Edinburgh; Reino Unido
Fil: Loftus, Brendan. University College Dublin; Irlanda
Fil: Recio Balsells, Alejandro Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina
Fil: Labadie, Guillermo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina
Fil: Gordon, Stephen V.. University College Dublin; Irlanda
Fil: Morbidoni, Héctor Ricardo. Universidad Nacional de Rosario; Argentina
description Clinical isolates of Mycobacterium tuberculosis and Mycobacterium bovis are differentially susceptible to 2-Thiophen Hydrazide (TCH); however its mechanism of action or the reasons for that difference are unknown. We report herein that under our experimental conditions, TCH inhibits M. tuberculosis in solid but not in liquid medium, and that in spite of resembling Isoniazid and Ethionamide, it does not affect mycolic acid synthesis. To understand the mechanisms of action of TCH we isolated M. tuberculosis TCH resistant mutants which fell into two groups; one resistant to TCH and Isoniazid but not to Ethionamide or Triclosan, and the other resistant only to TCH with no, or marginal, cross resistance to Isoniazid. A S315T katG mutation conferred resistance to TCH while katG expression from a plasmid reduced M. tuberculosis MIC to this drug, suggesting a possible involvement of KatG in TCH activation. Whole genome sequencing of mutants from this second group revealed a single mutation in the alkylhydroperoxide reductase ahpC promoter locus in half of the mutants, while the remaining contained mutations in dispensable genes. This is the first report of the genetics underlying the action of TCH and of the involvement of ahpC as the sole basis for resistance to an anti-tubercular compound.
publishDate 2018
dc.date.none.fl_str_mv 2018-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/91966
Franceschelli, Jorgelina Judith; Belardinelli, Juan Manuel; Tong, Ping; Loftus, Brendan; Recio Balsells, Alejandro Iván; et al.; A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide; Churchill Livingstone; Tuberculosis (Edinb); 112; 9-2018; 69-78
1472-9792
CONICET Digital
CONICET
url http://hdl.handle.net/11336/91966
identifier_str_mv Franceschelli, Jorgelina Judith; Belardinelli, Juan Manuel; Tong, Ping; Loftus, Brendan; Recio Balsells, Alejandro Iván; et al.; A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide; Churchill Livingstone; Tuberculosis (Edinb); 112; 9-2018; 69-78
1472-9792
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.tube.2018.08.001
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S1472979218301598
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Churchill Livingstone
publisher.none.fl_str_mv Churchill Livingstone
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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