New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae

Streptococcus pneumoniae has two type II DNA-topoisomerases (DNA-gyrase and DNA topoisomerase IV) and a single type I enzyme (DNA-topoisomerase I, TopA), as demonstrated here. Although fluoroquinolones target type II enzymes, antibiotics efficiently targeting TopA have not yet been reported. Eightee...

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Autores: García Esteban, María Teresa, Blázquez, María Amparo, Ferrándiz, María José, Sanz, María Jesús, Silva Martín, Noella, Hermoso, Juan Antonio, G. de la Campa, Adela
Tipo de recurso: artículo
Fecha de publicación:2011
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/125406
Acceso en línea:https://hdl.handle.net/20.500.14352/125406
Access Level:acceso abierto
Palabra clave:579.61
616.9
577.18.08
615.01/.03
577.2
Antibiotics
DNA Topoisomerase
DNA Topology
Drug Resistance
Protein-DNA Interaction
Microbiología (Biología)
Enfermedades infecciosas
Biología molecular (Biología)
2414 Microbiología
3205.05 Enfermedades Infecciosas
3302.01 Tecnología de Los Antibióticos
2302.21 Biología Molecular
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oai_identifier_str oai:docta.ucm.es:20.500.14352/125406
network_acronym_str ES
network_name_str España
repository_id_str
spelling New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniaeGarcía Esteban, María TeresaBlázquez, María AmparoFerrándiz, María JoséSanz, María JesúsSilva Martín, NoellaHermoso, Juan AntonioG. de la Campa, Adela579.61616.9577.18.08615.01/.03577.2AntibioticsDNA TopoisomeraseDNA TopologyDrug ResistanceProtein-DNA InteractionMicrobiología (Biología)Enfermedades infecciosasBiología molecular (Biología)2414 Microbiología3205.05 Enfermedades Infecciosas3302.01 Tecnología de Los Antibióticos2302.21 Biología MolecularStreptococcus pneumoniae has two type II DNA-topoisomerases (DNA-gyrase and DNA topoisomerase IV) and a single type I enzyme (DNA-topoisomerase I, TopA), as demonstrated here. Although fluoroquinolones target type II enzymes, antibiotics efficiently targeting TopA have not yet been reported. Eighteen alkaloids (seven aporphine and 11 phenanthrenes) were semisynthesized from boldine and used to test inhibition both of TopA activity and of cell growth. Two phenanthrenes (seconeolitsine and N-methyl-seconeolitsine) effectively inhibited both TopA activity and cell growth at equivalent concentrations (∼17 μm). Evidence for in vivo TopA targeting by seconeolitsine was provided by the protection of growth inhibition in a S. pneumoniae culture in which the enzyme was overproduced. Additionally, hypernegative supercoiling was observed in an internal plasmid after drug treatment. Furthermore, a model of pneumococcal TopA was made based on the crystal structure of Escherichia coli TopA. Docking calculations indicated strong interactions of the alkaloids with the nucleotide-binding site in the closed protein conformation, which correlated with their inhibitory effect. Finally, although seconeolitsine and N-methyl-seconeolitsine inhibited TopA and bacterial growth, they did not affect human cell viability. Therefore, these new alkaloids can be envisaged as new therapeutic candidates for the treatment of S. pneumoniae infections resistant to other antibiotics.ElsevierUniversidad Complutense de Madrid20112011-02-2520112011-02-25journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/125406reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1254062026-06-02T12:44:21Z
dc.title.none.fl_str_mv New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
title New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
spellingShingle New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
García Esteban, María Teresa
579.61
616.9
577.18.08
615.01/.03
577.2
Antibiotics
DNA Topoisomerase
DNA Topology
Drug Resistance
Protein-DNA Interaction
Microbiología (Biología)
Enfermedades infecciosas
Biología molecular (Biología)
2414 Microbiología
3205.05 Enfermedades Infecciosas
3302.01 Tecnología de Los Antibióticos
2302.21 Biología Molecular
title_short New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
title_full New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
title_fullStr New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
title_full_unstemmed New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
title_sort New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
dc.creator.none.fl_str_mv García Esteban, María Teresa
Blázquez, María Amparo
Ferrándiz, María José
Sanz, María Jesús
Silva Martín, Noella
Hermoso, Juan Antonio
G. de la Campa, Adela
author García Esteban, María Teresa
author_facet García Esteban, María Teresa
Blázquez, María Amparo
Ferrándiz, María José
Sanz, María Jesús
Silva Martín, Noella
Hermoso, Juan Antonio
G. de la Campa, Adela
author_role author
author2 Blázquez, María Amparo
Ferrándiz, María José
Sanz, María Jesús
Silva Martín, Noella
Hermoso, Juan Antonio
G. de la Campa, Adela
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 579.61
616.9
577.18.08
615.01/.03
577.2
Antibiotics
DNA Topoisomerase
DNA Topology
Drug Resistance
Protein-DNA Interaction
Microbiología (Biología)
Enfermedades infecciosas
Biología molecular (Biología)
2414 Microbiología
3205.05 Enfermedades Infecciosas
3302.01 Tecnología de Los Antibióticos
2302.21 Biología Molecular
topic 579.61
616.9
577.18.08
615.01/.03
577.2
Antibiotics
DNA Topoisomerase
DNA Topology
Drug Resistance
Protein-DNA Interaction
Microbiología (Biología)
Enfermedades infecciosas
Biología molecular (Biología)
2414 Microbiología
3205.05 Enfermedades Infecciosas
3302.01 Tecnología de Los Antibióticos
2302.21 Biología Molecular
description Streptococcus pneumoniae has two type II DNA-topoisomerases (DNA-gyrase and DNA topoisomerase IV) and a single type I enzyme (DNA-topoisomerase I, TopA), as demonstrated here. Although fluoroquinolones target type II enzymes, antibiotics efficiently targeting TopA have not yet been reported. Eighteen alkaloids (seven aporphine and 11 phenanthrenes) were semisynthesized from boldine and used to test inhibition both of TopA activity and of cell growth. Two phenanthrenes (seconeolitsine and N-methyl-seconeolitsine) effectively inhibited both TopA activity and cell growth at equivalent concentrations (∼17 μm). Evidence for in vivo TopA targeting by seconeolitsine was provided by the protection of growth inhibition in a S. pneumoniae culture in which the enzyme was overproduced. Additionally, hypernegative supercoiling was observed in an internal plasmid after drug treatment. Furthermore, a model of pneumococcal TopA was made based on the crystal structure of Escherichia coli TopA. Docking calculations indicated strong interactions of the alkaloids with the nucleotide-binding site in the closed protein conformation, which correlated with their inhibitory effect. Finally, although seconeolitsine and N-methyl-seconeolitsine inhibited TopA and bacterial growth, they did not affect human cell viability. Therefore, these new alkaloids can be envisaged as new therapeutic candidates for the treatment of S. pneumoniae infections resistant to other antibiotics.
publishDate 2011
dc.date.none.fl_str_mv 2011
2011-02-25
2011
2011-02-25
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/125406
url https://hdl.handle.net/20.500.14352/125406
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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