Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis

Autores
Martini, María Carla; Alonso, Maria Natalia; Cafiero, Juan Hilario; Xiao, Junpei; Shell, Scarlet S.
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
In view of the urgent need for new antibiotics to treat human infections caused by multidrug-resistant pathogens, drug repurposing is gaining strength due to the relatively low research costs and shorter clinical trials. Such is the case of artemisinin, an antimalarial drug that has recently been shown to display activity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. To gain insight into how Mtb is affected by artemisinin, we used RNAseq to assess the impact of artemisinin on gene expression profiles, revealing the induction of several efflux pumps and the KstR2 regulon. To anticipate the artemisinin resistance-conferring mutations that could arise in clinical Mtb strains, we performed an in vitro evolution experiment in the presence of lethal concentrations of artemisinin. We obtained artemisinin-resistant isolates displaying different growth kinetics and drug phenotypes, suggesting that resistance evolved through different pathways. Whole-genome sequencing of nine isolates revealed alterations in the glpK and glpQ1 genes, both involved in glycerol metabolism, in seven and one strains, respectively. We then constructed a glpK mutant and found that loss of glpK increases artemisinin resistance only when glycerol is present as a major carbon source. Our results suggest that mutations in glycerol catabolism genes could be selected during the evolution of resistance to artemisinin when glycerol is available as a carbon source. These results add to recent findings of mutations and phase variants that reduce drug efficacy in carbon-source-dependent ways.
Fil: Martini, María Carla. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentina
Fil: Alonso, Maria Natalia. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; Argentina
Fil: Cafiero, Juan Hilario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentina
Fil: Xiao, Junpei. Worcester Polytechnic Institute; Estados Unidos
Fil: Shell, Scarlet S.. Worcester Polytechnic Institute; Estados Unidos
Materia
MYCOBACTERIUM TUBERCULOSIS
GLYCEROL METABOLISM
ARTEMISININ
GLPK
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/264279
Acceder
id CONICETDig_397a4f3eaacaf567c50e38578280ebb2
oai_identifier_str oai:ri.conicet.gov.ar:11336/264279
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosisMartini, María CarlaAlonso, Maria NataliaCafiero, Juan HilarioXiao, JunpeiShell, Scarlet S.MYCOBACTERIUM TUBERCULOSISGLYCEROL METABOLISMARTEMISININGLPKhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1In view of the urgent need for new antibiotics to treat human infections caused by multidrug-resistant pathogens, drug repurposing is gaining strength due to the relatively low research costs and shorter clinical trials. Such is the case of artemisinin, an antimalarial drug that has recently been shown to display activity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. To gain insight into how Mtb is affected by artemisinin, we used RNAseq to assess the impact of artemisinin on gene expression profiles, revealing the induction of several efflux pumps and the KstR2 regulon. To anticipate the artemisinin resistance-conferring mutations that could arise in clinical Mtb strains, we performed an in vitro evolution experiment in the presence of lethal concentrations of artemisinin. We obtained artemisinin-resistant isolates displaying different growth kinetics and drug phenotypes, suggesting that resistance evolved through different pathways. Whole-genome sequencing of nine isolates revealed alterations in the glpK and glpQ1 genes, both involved in glycerol metabolism, in seven and one strains, respectively. We then constructed a glpK mutant and found that loss of glpK increases artemisinin resistance only when glycerol is present as a major carbon source. Our results suggest that mutations in glycerol catabolism genes could be selected during the evolution of resistance to artemisinin when glycerol is available as a carbon source. These results add to recent findings of mutations and phase variants that reduce drug efficacy in carbon-source-dependent ways.Fil: Martini, María Carla. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Alonso, Maria Natalia. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; ArgentinaFil: Cafiero, Juan Hilario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Xiao, Junpei. Worcester Polytechnic Institute; Estados UnidosFil: Shell, Scarlet S.. Worcester Polytechnic Institute; Estados UnidosAmerican Society for Microbiology2024-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/264279Martini, María Carla; Alonso, Maria Natalia; Cafiero, Juan Hilario; Xiao, Junpei; Shell, Scarlet S.; Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 68; 10; 8-2024; 1-110066-4804CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/aac.00645-24info:eu-repo/semantics/altIdentifier/doi/10.1128/aac.00645-24info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:34:16Zoai:ri.conicet.gov.ar:11336/264279instacron: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:34982025-09-29 09:34:16.525CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis
title Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis
spellingShingle Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis
Martini, María Carla
MYCOBACTERIUM TUBERCULOSIS
GLYCEROL METABOLISM
ARTEMISININ
GLPK
title_short Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis
title_full Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis
title_fullStr Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis
title_full_unstemmed Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis
title_sort Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis
dc.creator.none.fl_str_mv Martini, María Carla
Alonso, Maria Natalia
Cafiero, Juan Hilario
Xiao, Junpei
Shell, Scarlet S.
author Martini, María Carla
author_facet Martini, María Carla
Alonso, Maria Natalia
Cafiero, Juan Hilario
Xiao, Junpei
Shell, Scarlet S.
author_role author
author2 Alonso, Maria Natalia
Cafiero, Juan Hilario
Xiao, Junpei
Shell, Scarlet S.
author2_role author
author
author
author
dc.subject.none.fl_str_mv MYCOBACTERIUM TUBERCULOSIS
GLYCEROL METABOLISM
ARTEMISININ
GLPK
topic MYCOBACTERIUM TUBERCULOSIS
GLYCEROL METABOLISM
ARTEMISININ
GLPK
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv In view of the urgent need for new antibiotics to treat human infections caused by multidrug-resistant pathogens, drug repurposing is gaining strength due to the relatively low research costs and shorter clinical trials. Such is the case of artemisinin, an antimalarial drug that has recently been shown to display activity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. To gain insight into how Mtb is affected by artemisinin, we used RNAseq to assess the impact of artemisinin on gene expression profiles, revealing the induction of several efflux pumps and the KstR2 regulon. To anticipate the artemisinin resistance-conferring mutations that could arise in clinical Mtb strains, we performed an in vitro evolution experiment in the presence of lethal concentrations of artemisinin. We obtained artemisinin-resistant isolates displaying different growth kinetics and drug phenotypes, suggesting that resistance evolved through different pathways. Whole-genome sequencing of nine isolates revealed alterations in the glpK and glpQ1 genes, both involved in glycerol metabolism, in seven and one strains, respectively. We then constructed a glpK mutant and found that loss of glpK increases artemisinin resistance only when glycerol is present as a major carbon source. Our results suggest that mutations in glycerol catabolism genes could be selected during the evolution of resistance to artemisinin when glycerol is available as a carbon source. These results add to recent findings of mutations and phase variants that reduce drug efficacy in carbon-source-dependent ways.
Fil: Martini, María Carla. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentina
Fil: Alonso, Maria Natalia. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; Argentina
Fil: Cafiero, Juan Hilario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentina
Fil: Xiao, Junpei. Worcester Polytechnic Institute; Estados Unidos
Fil: Shell, Scarlet S.. Worcester Polytechnic Institute; Estados Unidos
description In view of the urgent need for new antibiotics to treat human infections caused by multidrug-resistant pathogens, drug repurposing is gaining strength due to the relatively low research costs and shorter clinical trials. Such is the case of artemisinin, an antimalarial drug that has recently been shown to display activity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. To gain insight into how Mtb is affected by artemisinin, we used RNAseq to assess the impact of artemisinin on gene expression profiles, revealing the induction of several efflux pumps and the KstR2 regulon. To anticipate the artemisinin resistance-conferring mutations that could arise in clinical Mtb strains, we performed an in vitro evolution experiment in the presence of lethal concentrations of artemisinin. We obtained artemisinin-resistant isolates displaying different growth kinetics and drug phenotypes, suggesting that resistance evolved through different pathways. Whole-genome sequencing of nine isolates revealed alterations in the glpK and glpQ1 genes, both involved in glycerol metabolism, in seven and one strains, respectively. We then constructed a glpK mutant and found that loss of glpK increases artemisinin resistance only when glycerol is present as a major carbon source. Our results suggest that mutations in glycerol catabolism genes could be selected during the evolution of resistance to artemisinin when glycerol is available as a carbon source. These results add to recent findings of mutations and phase variants that reduce drug efficacy in carbon-source-dependent ways.
publishDate 2024
dc.date.none.fl_str_mv 2024-08
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/11336/264279
Martini, María Carla; Alonso, Maria Natalia; Cafiero, Juan Hilario; Xiao, Junpei; Shell, Scarlet S.; Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 68; 10; 8-2024; 1-11
0066-4804
CONICET Digital
CONICET
url http://hdl.handle.net/11336/264279
identifier_str_mv Martini, María Carla; Alonso, Maria Natalia; Cafiero, Juan Hilario; Xiao, Junpei; Shell, Scarlet S.; Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance in Mycobacterium tuberculosis; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 68; 10; 8-2024; 1-11
0066-4804
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/aac.00645-24
info:eu-repo/semantics/altIdentifier/doi/10.1128/aac.00645-24
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
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 13.070432

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