Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System

Autores
Carabajal, María Ayelén; Asquith, Christopher R. M.; Laitinen, Tuomo; Tizzard, Graham J.; Yim, Lucía; Rial, Analía; Chabalgoity, José A.; Zuercher, William J.; Garcia Vescovi, Eleonora
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental conditions, including the challenges that pathogenic bacteria face inside the host. The differential presence of TCS, present in bacteria but absent in the animal kingdom, makes them attractive targets in the search for new antibacterial compounds. In Salmonella enterica, the PhoP/PhoQ two-component system controls the expression of crucial phenotypes that define the ability of the pathogen to establish infection in the host. We now report the screening of 686 compounds from a GlaxoSmithKline published kinase inhibitor set in a high-throughput whole-cell assay that targets Salmonella enterica serovar Typhimurium PhoP/PhoQ. We identified a series of quinazoline compounds that showed selective and potent downregulation of PhoP/PhoQ-activated genes and define structural attributes required for their efficacy. We demonstrate that their bioactivity is due to repression of the PhoQ sensor autokinase activity mediated by interaction with its catalytic domain, acting as competitive inhibitors of ATP binding. While noncytotoxic, the hit molecules exhibit antivirulence effect by blockage of S. Typhimurium intramacrophage replication. Together, these features make these quinazoline compounds stand out as exciting leads to develop a therapeutic intervention to fight salmonellosis.
Fil: Carabajal, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Asquith, Christopher R. M.. University of North Carolina; Estados Unidos
Fil: Laitinen, Tuomo. University of North Carolina; Estados Unidos
Fil: Tizzard, Graham J.. University of North Carolina; Estados Unidos
Fil: Yim, Lucía. Universidad de la República; Uruguay
Fil: Rial, Analía. Universidad de la República; Uruguay
Fil: Chabalgoity, José A.. Universidad de la República; Uruguay
Fil: Zuercher, William J.. University of North Carolina; Estados Unidos
Fil: Garcia Vescovi, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Materia
ANTIVIRULENCE
DRUG DISCOVERY
PHOP/PHOQ TWO-COMPONENT SYSTEM
QUINAZOLINES
SALMONELLA
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:11336/182537
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/182537
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction SystemCarabajal, María AyelénAsquith, Christopher R. M.Laitinen, TuomoTizzard, Graham J.Yim, LucíaRial, AnalíaChabalgoity, José A.Zuercher, William J.Garcia Vescovi, EleonoraANTIVIRULENCEDRUG DISCOVERYPHOP/PHOQ TWO-COMPONENT SYSTEMQUINAZOLINESSALMONELLAhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental conditions, including the challenges that pathogenic bacteria face inside the host. The differential presence of TCS, present in bacteria but absent in the animal kingdom, makes them attractive targets in the search for new antibacterial compounds. In Salmonella enterica, the PhoP/PhoQ two-component system controls the expression of crucial phenotypes that define the ability of the pathogen to establish infection in the host. We now report the screening of 686 compounds from a GlaxoSmithKline published kinase inhibitor set in a high-throughput whole-cell assay that targets Salmonella enterica serovar Typhimurium PhoP/PhoQ. We identified a series of quinazoline compounds that showed selective and potent downregulation of PhoP/PhoQ-activated genes and define structural attributes required for their efficacy. We demonstrate that their bioactivity is due to repression of the PhoQ sensor autokinase activity mediated by interaction with its catalytic domain, acting as competitive inhibitors of ATP binding. While noncytotoxic, the hit molecules exhibit antivirulence effect by blockage of S. Typhimurium intramacrophage replication. Together, these features make these quinazoline compounds stand out as exciting leads to develop a therapeutic intervention to fight salmonellosis.Fil: Carabajal, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Asquith, Christopher R. M.. University of North Carolina; Estados UnidosFil: Laitinen, Tuomo. University of North Carolina; Estados UnidosFil: Tizzard, Graham J.. University of North Carolina; Estados UnidosFil: Yim, Lucía. Universidad de la República; UruguayFil: Rial, Analía. Universidad de la República; UruguayFil: Chabalgoity, José A.. Universidad de la República; UruguayFil: Zuercher, William J.. University of North Carolina; Estados UnidosFil: Garcia Vescovi, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaAmerican Society for Microbiology2019-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/182537Carabajal, María Ayelén; Asquith, Christopher R. M.; Laitinen, Tuomo; Tizzard, Graham J.; Yim, Lucía; et al.; Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 64; 1; 12-2019; 1-160066-4804CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://aac.asm.org/content/64/1/e01744-19info:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.01744-19info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:53:38Zoai:ri.conicet.gov.ar:11336/182537instacron: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:34982025-09-03 09:53:38.498CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
title Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
spellingShingle Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
Carabajal, María Ayelén
ANTIVIRULENCE
DRUG DISCOVERY
PHOP/PHOQ TWO-COMPONENT SYSTEM
QUINAZOLINES
SALMONELLA
title_short Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
title_full Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
title_fullStr Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
title_full_unstemmed Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
title_sort Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
dc.creator.none.fl_str_mv Carabajal, María Ayelén
Asquith, Christopher R. M.
Laitinen, Tuomo
Tizzard, Graham J.
Yim, Lucía
Rial, Analía
Chabalgoity, José A.
Zuercher, William J.
Garcia Vescovi, Eleonora
author Carabajal, María Ayelén
author_facet Carabajal, María Ayelén
Asquith, Christopher R. M.
Laitinen, Tuomo
Tizzard, Graham J.
Yim, Lucía
Rial, Analía
Chabalgoity, José A.
Zuercher, William J.
Garcia Vescovi, Eleonora
author_role author
author2 Asquith, Christopher R. M.
Laitinen, Tuomo
Tizzard, Graham J.
Yim, Lucía
Rial, Analía
Chabalgoity, José A.
Zuercher, William J.
Garcia Vescovi, Eleonora
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ANTIVIRULENCE
DRUG DISCOVERY
PHOP/PHOQ TWO-COMPONENT SYSTEM
QUINAZOLINES
SALMONELLA
topic ANTIVIRULENCE
DRUG DISCOVERY
PHOP/PHOQ TWO-COMPONENT SYSTEM
QUINAZOLINES
SALMONELLA
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental conditions, including the challenges that pathogenic bacteria face inside the host. The differential presence of TCS, present in bacteria but absent in the animal kingdom, makes them attractive targets in the search for new antibacterial compounds. In Salmonella enterica, the PhoP/PhoQ two-component system controls the expression of crucial phenotypes that define the ability of the pathogen to establish infection in the host. We now report the screening of 686 compounds from a GlaxoSmithKline published kinase inhibitor set in a high-throughput whole-cell assay that targets Salmonella enterica serovar Typhimurium PhoP/PhoQ. We identified a series of quinazoline compounds that showed selective and potent downregulation of PhoP/PhoQ-activated genes and define structural attributes required for their efficacy. We demonstrate that their bioactivity is due to repression of the PhoQ sensor autokinase activity mediated by interaction with its catalytic domain, acting as competitive inhibitors of ATP binding. While noncytotoxic, the hit molecules exhibit antivirulence effect by blockage of S. Typhimurium intramacrophage replication. Together, these features make these quinazoline compounds stand out as exciting leads to develop a therapeutic intervention to fight salmonellosis.
Fil: Carabajal, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Asquith, Christopher R. M.. University of North Carolina; Estados Unidos
Fil: Laitinen, Tuomo. University of North Carolina; Estados Unidos
Fil: Tizzard, Graham J.. University of North Carolina; Estados Unidos
Fil: Yim, Lucía. Universidad de la República; Uruguay
Fil: Rial, Analía. Universidad de la República; Uruguay
Fil: Chabalgoity, José A.. Universidad de la República; Uruguay
Fil: Zuercher, William J.. University of North Carolina; Estados Unidos
Fil: Garcia Vescovi, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
description The rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental conditions, including the challenges that pathogenic bacteria face inside the host. The differential presence of TCS, present in bacteria but absent in the animal kingdom, makes them attractive targets in the search for new antibacterial compounds. In Salmonella enterica, the PhoP/PhoQ two-component system controls the expression of crucial phenotypes that define the ability of the pathogen to establish infection in the host. We now report the screening of 686 compounds from a GlaxoSmithKline published kinase inhibitor set in a high-throughput whole-cell assay that targets Salmonella enterica serovar Typhimurium PhoP/PhoQ. We identified a series of quinazoline compounds that showed selective and potent downregulation of PhoP/PhoQ-activated genes and define structural attributes required for their efficacy. We demonstrate that their bioactivity is due to repression of the PhoQ sensor autokinase activity mediated by interaction with its catalytic domain, acting as competitive inhibitors of ATP binding. While noncytotoxic, the hit molecules exhibit antivirulence effect by blockage of S. Typhimurium intramacrophage replication. Together, these features make these quinazoline compounds stand out as exciting leads to develop a therapeutic intervention to fight salmonellosis.
publishDate 2019
dc.date.none.fl_str_mv 2019-12
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/11336/182537
Carabajal, María Ayelén; Asquith, Christopher R. M.; Laitinen, Tuomo; Tizzard, Graham J.; Yim, Lucía; et al.; Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 64; 1; 12-2019; 1-16
0066-4804
CONICET Digital
CONICET
url http://hdl.handle.net/11336/182537
identifier_str_mv Carabajal, María Ayelén; Asquith, Christopher R. M.; Laitinen, Tuomo; Tizzard, Graham J.; Yim, Lucía; et al.; Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 64; 1; 12-2019; 1-16
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://aac.asm.org/content/64/1/e01744-19
info:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.01744-19
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 13.13397

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