Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria

Autores
Corleto, Ingrid Merlina; Garavaglia, Matías Javier; Martínez, Melina María Belén; Weschenfeller, Melanie Elizabeth; Urrea Montes, Santiago; Aran, Martin; Pellizza Pena, Leonardo Agustín; Faccone, Diego Francisco; Maffia, Paulo Cesar
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background/Objectives: Colistin (polymyxin E) has re-emerged as a last-hope treatmentagainst MDR Gram-negative pathogens due to the development of extensively drugresistantGram-negative bacteria. Unfortunately, rapid global resistance towards colistin hasemerged, which represents a major public health concern. In this context (CBD), a lipophilicmolecule derived from Cannabis sativa, exhibits antimicrobial activity mainly againstGram-positive bacteria but is generally ineffective against Gram-negative species. However,synergistic antibacterial activity between CBD and polymyxin B has been reported. Theobjective of this work is to analyze the colistin–CBD synergy against clinically relevantGram-negative isolates displaying diverse mechanisms of colistin resistance and to explorethe basis of the possible mechanism of action involved in the first steps of this synergy.Methods: Microbiological assays, minimal inhibitory concentration, cell culture, synergytests by checker board and time kill, biofilm inhibition evaluation by crystal violet and MTT,SEM (scanning electron microscopy), molecules interaction analysis by nuclear magneticresonance (NMR). Results: The colistin–CBD combination displayed synergy in colistinresistant Gram-negative bacteria and also disrupted preformed biofilms and killed bacteriawithin them. Time-kill assays revealed rapid bactericidal activity and SEM showed mildsurface alterations on bacterial outer membranes after sublethal colistin monotherapy.Furthermore, a series of sequential treatment assays on colistin-resistant Escherichia colishowed that simultaneous exposure to both compounds was required for activity, asintroducing a washing step between treatments abolished the antibacterial effect. In orderto obtain deeper insight into this mechanism, NMR analyses were performed, revealingspecific molecular interactions between CBD and colistin molecules. Conclusions: Theseresults provide evidence for the first time that both molecules engage through a specificand structurally meaningful interaction and only display synergy when acting together oncolistin-resistant bacteria.
Fil: Corleto, Ingrid Merlina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garavaglia, Matías Javier. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Martínez, Melina María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina
Fil: Weschenfeller, Melanie Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina
Fil: Urrea Montes, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina
Fil: Aran, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Pellizza Pena, Leonardo Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Faccone, Diego Francisco. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Instituto Nacional de Enfermedades Infecciosas. Área de Antimicrobianos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Maffia, Paulo Cesar. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
COLISTIN
CANNABIDIOL
SYNERGY
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:11336/279625
Acceder
id CONICETDig_2e2f2470ab882a77f093b38eea81305b
oai_identifier_str oai:ri.conicet.gov.ar:11336/279625
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative BacteriaCorleto, Ingrid MerlinaGaravaglia, Matías JavierMartínez, Melina María BelénWeschenfeller, Melanie ElizabethUrrea Montes, SantiagoAran, MartinPellizza Pena, Leonardo AgustínFaccone, Diego FranciscoMaffia, Paulo CesarCOLISTINCANNABIDIOLSYNERGYhttps://purl.org/becyt/ford/3.5https://purl.org/becyt/ford/3Background/Objectives: Colistin (polymyxin E) has re-emerged as a last-hope treatmentagainst MDR Gram-negative pathogens due to the development of extensively drugresistantGram-negative bacteria. Unfortunately, rapid global resistance towards colistin hasemerged, which represents a major public health concern. In this context (CBD), a lipophilicmolecule derived from Cannabis sativa, exhibits antimicrobial activity mainly againstGram-positive bacteria but is generally ineffective against Gram-negative species. However,synergistic antibacterial activity between CBD and polymyxin B has been reported. Theobjective of this work is to analyze the colistin–CBD synergy against clinically relevantGram-negative isolates displaying diverse mechanisms of colistin resistance and to explorethe basis of the possible mechanism of action involved in the first steps of this synergy.Methods: Microbiological assays, minimal inhibitory concentration, cell culture, synergytests by checker board and time kill, biofilm inhibition evaluation by crystal violet and MTT,SEM (scanning electron microscopy), molecules interaction analysis by nuclear magneticresonance (NMR). Results: The colistin–CBD combination displayed synergy in colistinresistant Gram-negative bacteria and also disrupted preformed biofilms and killed bacteriawithin them. Time-kill assays revealed rapid bactericidal activity and SEM showed mildsurface alterations on bacterial outer membranes after sublethal colistin monotherapy.Furthermore, a series of sequential treatment assays on colistin-resistant Escherichia colishowed that simultaneous exposure to both compounds was required for activity, asintroducing a washing step between treatments abolished the antibacterial effect. In orderto obtain deeper insight into this mechanism, NMR analyses were performed, revealingspecific molecular interactions between CBD and colistin molecules. Conclusions: Theseresults provide evidence for the first time that both molecules engage through a specificand structurally meaningful interaction and only display synergy when acting together oncolistin-resistant bacteria.Fil: Corleto, Ingrid Merlina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garavaglia, Matías Javier. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martínez, Melina María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; ArgentinaFil: Weschenfeller, Melanie Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; ArgentinaFil: Urrea Montes, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; ArgentinaFil: Aran, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Pellizza Pena, Leonardo Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Faccone, Diego Francisco. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Instituto Nacional de Enfermedades Infecciosas. Área de Antimicrobianos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Maffia, Paulo Cesar. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaMDPI2025-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/279625Corleto, Ingrid Merlina; Garavaglia, Matías Javier; Martínez, Melina María Belén; Weschenfeller, Melanie Elizabeth; Urrea Montes, Santiago; et al.; Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria; MDPI; Pharmaceutics; 18; 1; 12-2025; 1-191999-4923CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1999-4923/18/1/51info:eu-repo/semantics/altIdentifier/doi/10.3390/pharmaceutics18010051info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-26T10:22:13Zoai:ri.conicet.gov.ar:11336/279625instacron: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:34982026-02-26 10:22:14.192CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria
title Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria
spellingShingle Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria
Corleto, Ingrid Merlina
COLISTIN
CANNABIDIOL
SYNERGY
title_short Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria
title_full Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria
title_fullStr Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria
title_full_unstemmed Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria
title_sort Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria
dc.creator.none.fl_str_mv Corleto, Ingrid Merlina
Garavaglia, Matías Javier
Martínez, Melina María Belén
Weschenfeller, Melanie Elizabeth
Urrea Montes, Santiago
Aran, Martin
Pellizza Pena, Leonardo Agustín
Faccone, Diego Francisco
Maffia, Paulo Cesar
author Corleto, Ingrid Merlina
author_facet Corleto, Ingrid Merlina
Garavaglia, Matías Javier
Martínez, Melina María Belén
Weschenfeller, Melanie Elizabeth
Urrea Montes, Santiago
Aran, Martin
Pellizza Pena, Leonardo Agustín
Faccone, Diego Francisco
Maffia, Paulo Cesar
author_role author
author2 Garavaglia, Matías Javier
Martínez, Melina María Belén
Weschenfeller, Melanie Elizabeth
Urrea Montes, Santiago
Aran, Martin
Pellizza Pena, Leonardo Agustín
Faccone, Diego Francisco
Maffia, Paulo Cesar
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv COLISTIN
CANNABIDIOL
SYNERGY
topic COLISTIN
CANNABIDIOL
SYNERGY
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.5
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background/Objectives: Colistin (polymyxin E) has re-emerged as a last-hope treatmentagainst MDR Gram-negative pathogens due to the development of extensively drugresistantGram-negative bacteria. Unfortunately, rapid global resistance towards colistin hasemerged, which represents a major public health concern. In this context (CBD), a lipophilicmolecule derived from Cannabis sativa, exhibits antimicrobial activity mainly againstGram-positive bacteria but is generally ineffective against Gram-negative species. However,synergistic antibacterial activity between CBD and polymyxin B has been reported. Theobjective of this work is to analyze the colistin–CBD synergy against clinically relevantGram-negative isolates displaying diverse mechanisms of colistin resistance and to explorethe basis of the possible mechanism of action involved in the first steps of this synergy.Methods: Microbiological assays, minimal inhibitory concentration, cell culture, synergytests by checker board and time kill, biofilm inhibition evaluation by crystal violet and MTT,SEM (scanning electron microscopy), molecules interaction analysis by nuclear magneticresonance (NMR). Results: The colistin–CBD combination displayed synergy in colistinresistant Gram-negative bacteria and also disrupted preformed biofilms and killed bacteriawithin them. Time-kill assays revealed rapid bactericidal activity and SEM showed mildsurface alterations on bacterial outer membranes after sublethal colistin monotherapy.Furthermore, a series of sequential treatment assays on colistin-resistant Escherichia colishowed that simultaneous exposure to both compounds was required for activity, asintroducing a washing step between treatments abolished the antibacterial effect. In orderto obtain deeper insight into this mechanism, NMR analyses were performed, revealingspecific molecular interactions between CBD and colistin molecules. Conclusions: Theseresults provide evidence for the first time that both molecules engage through a specificand structurally meaningful interaction and only display synergy when acting together oncolistin-resistant bacteria.
Fil: Corleto, Ingrid Merlina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garavaglia, Matías Javier. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Martínez, Melina María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina
Fil: Weschenfeller, Melanie Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina
Fil: Urrea Montes, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina
Fil: Aran, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Pellizza Pena, Leonardo Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Faccone, Diego Francisco. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Instituto Nacional de Enfermedades Infecciosas. Área de Antimicrobianos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Maffia, Paulo Cesar. Universidad Nacional de Hurlingham. Instituto de Biotecnologia.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Background/Objectives: Colistin (polymyxin E) has re-emerged as a last-hope treatmentagainst MDR Gram-negative pathogens due to the development of extensively drugresistantGram-negative bacteria. Unfortunately, rapid global resistance towards colistin hasemerged, which represents a major public health concern. In this context (CBD), a lipophilicmolecule derived from Cannabis sativa, exhibits antimicrobial activity mainly againstGram-positive bacteria but is generally ineffective against Gram-negative species. However,synergistic antibacterial activity between CBD and polymyxin B has been reported. Theobjective of this work is to analyze the colistin–CBD synergy against clinically relevantGram-negative isolates displaying diverse mechanisms of colistin resistance and to explorethe basis of the possible mechanism of action involved in the first steps of this synergy.Methods: Microbiological assays, minimal inhibitory concentration, cell culture, synergytests by checker board and time kill, biofilm inhibition evaluation by crystal violet and MTT,SEM (scanning electron microscopy), molecules interaction analysis by nuclear magneticresonance (NMR). Results: The colistin–CBD combination displayed synergy in colistinresistant Gram-negative bacteria and also disrupted preformed biofilms and killed bacteriawithin them. Time-kill assays revealed rapid bactericidal activity and SEM showed mildsurface alterations on bacterial outer membranes after sublethal colistin monotherapy.Furthermore, a series of sequential treatment assays on colistin-resistant Escherichia colishowed that simultaneous exposure to both compounds was required for activity, asintroducing a washing step between treatments abolished the antibacterial effect. In orderto obtain deeper insight into this mechanism, NMR analyses were performed, revealingspecific molecular interactions between CBD and colistin molecules. Conclusions: Theseresults provide evidence for the first time that both molecules engage through a specificand structurally meaningful interaction and only display synergy when acting together oncolistin-resistant bacteria.
publishDate 2025
dc.date.none.fl_str_mv 2025-12
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/11336/279625
Corleto, Ingrid Merlina; Garavaglia, Matías Javier; Martínez, Melina María Belén; Weschenfeller, Melanie Elizabeth; Urrea Montes, Santiago; et al.; Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria; MDPI; Pharmaceutics; 18; 1; 12-2025; 1-19
1999-4923
CONICET Digital
CONICET
url http://hdl.handle.net/11336/279625
identifier_str_mv Corleto, Ingrid Merlina; Garavaglia, Matías Javier; Martínez, Melina María Belén; Weschenfeller, Melanie Elizabeth; Urrea Montes, Santiago; et al.; Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria; MDPI; Pharmaceutics; 18; 1; 12-2025; 1-19
1999-4923
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://www.mdpi.com/1999-4923/18/1/51
info:eu-repo/semantics/altIdentifier/doi/10.3390/pharmaceutics18010051
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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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 MDPI
publisher.none.fl_str_mv MDPI
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reponame_str CONICET Digital (CONICET)
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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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