An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli

Autores
Larzabal, Mariano; Baldoni, Hector A.; Suvire, Fernando D.; Curto, Lucrecia M.; Gomez, Gabriela E.; Marques Da Silva, Wanderson; Giudicessi, Silvana L.; Camperi, Silvia A.; Delfino, Jose M.; Cataldi, Angel Adrian; Enriz, Daniel
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Human pathogenic gram‐negative bacteria, such as enteropathogenic Escherichia coli (EPEC), rely on type III secretion systems (T3SS) to translocate virulence factors directly into host cells. The coiled‐coil domains present in the structural proteins of T3SS are conformed by amphipathic alpha‐helical structures that play an important role in the protein‐protein interaction and are essential for the assembly of the translocation complex. To investigate the inhibitory capacity of these domains on the T3SS of EPEC, we synthesized peptides between 7 and 34 amino acids based on the coiled‐coil domains of proteins that make up this secretion system. This analysis was performed through in vitro hemolysis assays by assessing the reduction of T3SS‐dependent red blood cell lysis in the presence of the synthesized peptides. After confirming its inhibitory capacity, we performed molecular modeling assays using combined techniques, docking‐molecular dynamic simulations, and quantum‐mechanic calculations of the various peptide‐protein complexes, to improve the affinity of the peptides to the target proteins selected from T3SS. These techniques allowed us to demonstrate that the peptides with greater inhibitory activity, directed against the coiled‐coil domain of the C‐terminal region of EspA, present favorable hydrophobic and hydrogen bond molecular interactions. Particularly, the hydrogen bond component is responsible for the stabilization of the peptide‐protein complex. This study demonstrates that compounds targeting T3SS from pathogenic bacteria can indeed inhibit bacterial infection by presenting a higher specificity than broad‐spectrum antibiotics. In turn, these peptides could be taken as initial structures to design and synthesize new compounds that mimic their inhibitory pharmacophoric pattern.
Instituto de Biotecnología
Fil: Larzabal, Mariano.Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Baldoni, Hector A. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Matemática Aplicada San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Suvire, Fernando D. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Curto, Lucrecia M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gomez, Gabriela E. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Marques Da Silva, Wanderson. Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Giudicessi, Silvana L. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Camperi, Silvia A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Delfino, Jose M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cataldi, Angel Adrian. Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Enriz, Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fuente
Journal of Peptide Science 25 (3) : e3149 (Marzo 2019)
Materia
Pathogenic Viruses
Peptides
Virus Patógenos
Escherichia coli
Péptidos
Nivel de accesibilidad
acceso restringido
Condiciones de uso
Repositorio
INTA Digital (INTA)
Institución
Instituto Nacional de Tecnología Agropecuaria
OAI Identificador
oai:localhost:20.500.12123/4808
Acceder
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oai_identifier_str oai:localhost:20.500.12123/4808
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network_name_str INTA Digital (INTA)
spelling An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coliLarzabal, MarianoBaldoni, Hector A.Suvire, Fernando D.Curto, Lucrecia M.Gomez, Gabriela E.Marques Da Silva, WandersonGiudicessi, Silvana L.Camperi, Silvia A.Delfino, Jose M.Cataldi, Angel AdrianEnriz, DanielPathogenic VirusesPeptidesVirus PatógenosEscherichia coliPéptidosHuman pathogenic gram‐negative bacteria, such as enteropathogenic Escherichia coli (EPEC), rely on type III secretion systems (T3SS) to translocate virulence factors directly into host cells. The coiled‐coil domains present in the structural proteins of T3SS are conformed by amphipathic alpha‐helical structures that play an important role in the protein‐protein interaction and are essential for the assembly of the translocation complex. To investigate the inhibitory capacity of these domains on the T3SS of EPEC, we synthesized peptides between 7 and 34 amino acids based on the coiled‐coil domains of proteins that make up this secretion system. This analysis was performed through in vitro hemolysis assays by assessing the reduction of T3SS‐dependent red blood cell lysis in the presence of the synthesized peptides. After confirming its inhibitory capacity, we performed molecular modeling assays using combined techniques, docking‐molecular dynamic simulations, and quantum‐mechanic calculations of the various peptide‐protein complexes, to improve the affinity of the peptides to the target proteins selected from T3SS. These techniques allowed us to demonstrate that the peptides with greater inhibitory activity, directed against the coiled‐coil domain of the C‐terminal region of EspA, present favorable hydrophobic and hydrogen bond molecular interactions. Particularly, the hydrogen bond component is responsible for the stabilization of the peptide‐protein complex. This study demonstrates that compounds targeting T3SS from pathogenic bacteria can indeed inhibit bacterial infection by presenting a higher specificity than broad‐spectrum antibiotics. In turn, these peptides could be taken as initial structures to design and synthesize new compounds that mimic their inhibitory pharmacophoric pattern.Instituto de BiotecnologíaFil: Larzabal, Mariano.Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Baldoni, Hector A. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Matemática Aplicada San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Suvire, Fernando D. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Curto, Lucrecia M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gomez, Gabriela E. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marques Da Silva, Wanderson. Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Giudicessi, Silvana L. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Camperi, Silvia A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Delfino, Jose M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cataldi, Angel Adrian. Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Enriz, Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaWiley2019-04-03T17:07:26Z2019-04-03T17:07:26Z2019-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttps://onlinelibrary.wiley.com/doi/abs/10.1002/psc.3149http://hdl.handle.net/20.500.12123/48081099-1387https://doi.org/10.1002/psc.3149Journal of Peptide Science 25 (3) : e3149 (Marzo 2019)reponame:INTA Digital (INTA)instname:Instituto Nacional de Tecnología Agropecuariaenginfo:eu-repo/semantics/restrictedAccess2025-09-11T10:22:59Zoai:localhost:20.500.12123/4808instacron:INTAInstitucionalhttp://repositorio.inta.gob.ar/Organismo científico-tecnológicoNo correspondehttp://repositorio.inta.gob.ar/oai/requesttripaldi.nicolas@inta.gob.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:l2025-09-11 10:23:00.244INTA Digital (INTA) - Instituto Nacional de Tecnología Agropecuariafalse
dc.title.none.fl_str_mv An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
title An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
spellingShingle An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
Larzabal, Mariano
Pathogenic Viruses
Peptides
Virus Patógenos
Escherichia coli
Péptidos
title_short An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
title_full An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
title_fullStr An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
title_full_unstemmed An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
title_sort An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
dc.creator.none.fl_str_mv Larzabal, Mariano
Baldoni, Hector A.
Suvire, Fernando D.
Curto, Lucrecia M.
Gomez, Gabriela E.
Marques Da Silva, Wanderson
Giudicessi, Silvana L.
Camperi, Silvia A.
Delfino, Jose M.
Cataldi, Angel Adrian
Enriz, Daniel
author Larzabal, Mariano
author_facet Larzabal, Mariano
Baldoni, Hector A.
Suvire, Fernando D.
Curto, Lucrecia M.
Gomez, Gabriela E.
Marques Da Silva, Wanderson
Giudicessi, Silvana L.
Camperi, Silvia A.
Delfino, Jose M.
Cataldi, Angel Adrian
Enriz, Daniel
author_role author
author2 Baldoni, Hector A.
Suvire, Fernando D.
Curto, Lucrecia M.
Gomez, Gabriela E.
Marques Da Silva, Wanderson
Giudicessi, Silvana L.
Camperi, Silvia A.
Delfino, Jose M.
Cataldi, Angel Adrian
Enriz, Daniel
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Pathogenic Viruses
Peptides
Virus Patógenos
Escherichia coli
Péptidos
topic Pathogenic Viruses
Peptides
Virus Patógenos
Escherichia coli
Péptidos
dc.description.none.fl_txt_mv Human pathogenic gram‐negative bacteria, such as enteropathogenic Escherichia coli (EPEC), rely on type III secretion systems (T3SS) to translocate virulence factors directly into host cells. The coiled‐coil domains present in the structural proteins of T3SS are conformed by amphipathic alpha‐helical structures that play an important role in the protein‐protein interaction and are essential for the assembly of the translocation complex. To investigate the inhibitory capacity of these domains on the T3SS of EPEC, we synthesized peptides between 7 and 34 amino acids based on the coiled‐coil domains of proteins that make up this secretion system. This analysis was performed through in vitro hemolysis assays by assessing the reduction of T3SS‐dependent red blood cell lysis in the presence of the synthesized peptides. After confirming its inhibitory capacity, we performed molecular modeling assays using combined techniques, docking‐molecular dynamic simulations, and quantum‐mechanic calculations of the various peptide‐protein complexes, to improve the affinity of the peptides to the target proteins selected from T3SS. These techniques allowed us to demonstrate that the peptides with greater inhibitory activity, directed against the coiled‐coil domain of the C‐terminal region of EspA, present favorable hydrophobic and hydrogen bond molecular interactions. Particularly, the hydrogen bond component is responsible for the stabilization of the peptide‐protein complex. This study demonstrates that compounds targeting T3SS from pathogenic bacteria can indeed inhibit bacterial infection by presenting a higher specificity than broad‐spectrum antibiotics. In turn, these peptides could be taken as initial structures to design and synthesize new compounds that mimic their inhibitory pharmacophoric pattern.
Instituto de Biotecnología
Fil: Larzabal, Mariano.Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Baldoni, Hector A. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Matemática Aplicada San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Suvire, Fernando D. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Curto, Lucrecia M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gomez, Gabriela E. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Marques Da Silva, Wanderson. Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Giudicessi, Silvana L. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Camperi, Silvia A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Delfino, Jose M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cataldi, Angel Adrian. Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Enriz, Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Human pathogenic gram‐negative bacteria, such as enteropathogenic Escherichia coli (EPEC), rely on type III secretion systems (T3SS) to translocate virulence factors directly into host cells. The coiled‐coil domains present in the structural proteins of T3SS are conformed by amphipathic alpha‐helical structures that play an important role in the protein‐protein interaction and are essential for the assembly of the translocation complex. To investigate the inhibitory capacity of these domains on the T3SS of EPEC, we synthesized peptides between 7 and 34 amino acids based on the coiled‐coil domains of proteins that make up this secretion system. This analysis was performed through in vitro hemolysis assays by assessing the reduction of T3SS‐dependent red blood cell lysis in the presence of the synthesized peptides. After confirming its inhibitory capacity, we performed molecular modeling assays using combined techniques, docking‐molecular dynamic simulations, and quantum‐mechanic calculations of the various peptide‐protein complexes, to improve the affinity of the peptides to the target proteins selected from T3SS. These techniques allowed us to demonstrate that the peptides with greater inhibitory activity, directed against the coiled‐coil domain of the C‐terminal region of EspA, present favorable hydrophobic and hydrogen bond molecular interactions. Particularly, the hydrogen bond component is responsible for the stabilization of the peptide‐protein complex. This study demonstrates that compounds targeting T3SS from pathogenic bacteria can indeed inhibit bacterial infection by presenting a higher specificity than broad‐spectrum antibiotics. In turn, these peptides could be taken as initial structures to design and synthesize new compounds that mimic their inhibitory pharmacophoric pattern.
publishDate 2019
dc.date.none.fl_str_mv 2019-04-03T17:07:26Z
2019-04-03T17:07:26Z
2019-03
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 https://onlinelibrary.wiley.com/doi/abs/10.1002/psc.3149
http://hdl.handle.net/20.500.12123/4808
1099-1387
https://doi.org/10.1002/psc.3149
url https://onlinelibrary.wiley.com/doi/abs/10.1002/psc.3149
http://hdl.handle.net/20.500.12123/4808
https://doi.org/10.1002/psc.3149
identifier_str_mv 1099-1387
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/restrictedAccess
eu_rights_str_mv restrictedAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv Journal of Peptide Science 25 (3) : e3149 (Marzo 2019)
reponame:INTA Digital (INTA)
instname:Instituto Nacional de Tecnología Agropecuaria
reponame_str INTA Digital (INTA)
collection INTA Digital (INTA)
instname_str Instituto Nacional de Tecnología Agropecuaria
repository.name.fl_str_mv INTA Digital (INTA) - Instituto Nacional de Tecnología Agropecuaria
repository.mail.fl_str_mv tripaldi.nicolas@inta.gob.ar
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