Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms

Abstract Microbial biofilms are involved in a number of infections that cannot be cured, as microbes in biofilms resist host immune defenses and antibiotic therapies. With no strict biofilm-antibiotic in the current pipelines, there is an unmet need for drug candidates that enable the current antibi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jens Bo Andersen, Louise Dahl Hultqvist, Charlotte Uldahl Jansen, Tim Holm Jakobsen, Martin Nilsson, Morten Rybtke, Jesper Uhd, Blaine Gabriel Fritz, Roland Seifert, Jens Berthelsen, Thomas Eiland Nielsen, Katrine Qvortrup, Michael Givskov, Tim Tolker-Nielsen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Microbial ecology QR100-130
Acceso en línea:	https://doaj.org/article/eda8b498ebe14f64949aa92898bfab95
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:eda8b498ebe14f64949aa92898bfab95
record_format	dspace
spelling	oai:doaj.org-article:eda8b498ebe14f64949aa92898bfab952021-12-02T16:24:51ZIdentification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms10.1038/s41522-021-00225-42055-5008https://doaj.org/article/eda8b498ebe14f64949aa92898bfab952021-07-01T00:00:00Zhttps://doi.org/10.1038/s41522-021-00225-4https://doaj.org/toc/2055-5008Abstract Microbial biofilms are involved in a number of infections that cannot be cured, as microbes in biofilms resist host immune defenses and antibiotic therapies. With no strict biofilm-antibiotic in the current pipelines, there is an unmet need for drug candidates that enable the current antibiotics to eradicate bacteria in biofilms. We used high-throughput screening to identify chemical compounds that reduce the intracellular c-di-GMP content in Pseudomonas aeruginosa. This led to the identification of a small molecule that efficiently depletes P. aeruginosa for c-di-GMP, inhibits biofilm formation, and disperses established biofilm. A combination of our lead compound with standard of care antibiotics showed improved eradication of an implant-associated infection established in mice. Genetic analyses provided evidence that the anti-biofilm compound stimulates the activity of the c-di-GMP phosphodiesterase BifA in P. aeruginosa. Our work constitutes a proof of concept for c-di-GMP phosphodiesterase-activating drugs administered in combination with antibiotics as a viable treatment strategy for otherwise recalcitrant infections.Jens Bo AndersenLouise Dahl HultqvistCharlotte Uldahl JansenTim Holm JakobsenMartin NilssonMorten RybtkeJesper UhdBlaine Gabriel FritzRoland SeifertJens BerthelsenThomas Eiland NielsenKatrine QvortrupMichael GivskovTim Tolker-NielsenNature PortfolioarticleMicrobial ecologyQR100-130ENnpj Biofilms and Microbiomes, Vol 7, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbial ecology QR100-130
spellingShingle	Microbial ecology QR100-130 Jens Bo Andersen Louise Dahl Hultqvist Charlotte Uldahl Jansen Tim Holm Jakobsen Martin Nilsson Morten Rybtke Jesper Uhd Blaine Gabriel Fritz Roland Seifert Jens Berthelsen Thomas Eiland Nielsen Katrine Qvortrup Michael Givskov Tim Tolker-Nielsen Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms
description	Abstract Microbial biofilms are involved in a number of infections that cannot be cured, as microbes in biofilms resist host immune defenses and antibiotic therapies. With no strict biofilm-antibiotic in the current pipelines, there is an unmet need for drug candidates that enable the current antibiotics to eradicate bacteria in biofilms. We used high-throughput screening to identify chemical compounds that reduce the intracellular c-di-GMP content in Pseudomonas aeruginosa. This led to the identification of a small molecule that efficiently depletes P. aeruginosa for c-di-GMP, inhibits biofilm formation, and disperses established biofilm. A combination of our lead compound with standard of care antibiotics showed improved eradication of an implant-associated infection established in mice. Genetic analyses provided evidence that the anti-biofilm compound stimulates the activity of the c-di-GMP phosphodiesterase BifA in P. aeruginosa. Our work constitutes a proof of concept for c-di-GMP phosphodiesterase-activating drugs administered in combination with antibiotics as a viable treatment strategy for otherwise recalcitrant infections.
format	article
author	Jens Bo Andersen Louise Dahl Hultqvist Charlotte Uldahl Jansen Tim Holm Jakobsen Martin Nilsson Morten Rybtke Jesper Uhd Blaine Gabriel Fritz Roland Seifert Jens Berthelsen Thomas Eiland Nielsen Katrine Qvortrup Michael Givskov Tim Tolker-Nielsen
author_facet	Jens Bo Andersen Louise Dahl Hultqvist Charlotte Uldahl Jansen Tim Holm Jakobsen Martin Nilsson Morten Rybtke Jesper Uhd Blaine Gabriel Fritz Roland Seifert Jens Berthelsen Thomas Eiland Nielsen Katrine Qvortrup Michael Givskov Tim Tolker-Nielsen
author_sort	Jens Bo Andersen
title	Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms
title_short	Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms
title_full	Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms
title_fullStr	Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms
title_full_unstemmed	Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms
title_sort	identification of small molecules that interfere with c-di-gmp signaling and induce dispersal of pseudomonas aeruginosa biofilms
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/eda8b498ebe14f64949aa92898bfab95
work_keys_str_mv	AT jensboandersen identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT louisedahlhultqvist identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT charlotteuldahljansen identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT timholmjakobsen identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT martinnilsson identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT mortenrybtke identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT jesperuhd identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT blainegabrielfritz identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT rolandseifert identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT jensberthelsen identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT thomaseilandnielsen identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT katrineqvortrup identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT michaelgivskov identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms AT timtolkernielsen identificationofsmallmoleculesthatinterferewithcdigmpsignalingandinducedispersalofpseudomonasaeruginosabiofilms
_version_	1718384144977756160

Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms

Ejemplares similares