Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections

Infections caused by Staphylococcus aureus pose a serious and sometimes fatal health issue. With the aim of exploring a novel therapeutic approach, we chose GraXRS, a Two-Component System (TCS) that determines bacterial resilience against host innate immune barriers, as an alternative target to disa...

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Autores: Prieto Mariscal, Juana María, Rapún Araiz, Beatriz, Gil Puig, Carmen, Penadés, José R., Lasa Uzcudun, Íñigo, Latasa Osta, Cristina
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad Pública de Navarra
Repositorio:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
OAI Identifier:oai:academica-e.unavarra.es:2454/39698
Acceso en línea:https://hdl.handle.net/2454/39698
Access Level:acceso abierto
Palabra clave:Staphylococcus aureus
GraXRS
Two component system
Verteporfin
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spelling Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infectionsPrieto Mariscal, Juana MaríaRapún Araiz, BeatrizGil Puig, CarmenPenadés, José R.Lasa Uzcudun, ÍñigoLatasa Osta, CristinaStaphylococcus aureusGraXRSTwo component systemVerteporfinInfections caused by Staphylococcus aureus pose a serious and sometimes fatal health issue. With the aim of exploring a novel therapeutic approach, we chose GraXRS, a Two-Component System (TCS) that determines bacterial resilience against host innate immune barriers, as an alternative target to disarm S. aureus. Following a drug repurposing methodology, and taking advantage of a singular staphylococcal strain that lacks the whole TCS machinery but the target one, we screened 1.280 offpatent FDA-approved drug for GraXRS inhibition. Reinforcing the connection between this signaling pathway and redox sensing, we found that antioxidant and redox-active molecules were capable of reducing the expression of the GraXRS regulon. Among all the compounds, verteporfin (VER) was really efficient in enhancing PMN-mediated bacterial killing, while topical administration of such drug in a murine model of surgical wound infection significantly reduced the bacterial load. Experiments relying on the chemical mimicry existing between VER and heme group suggest that redox active residue C227 of GraS participates in the inhibition exerted by this FDA-approved drug. Based on these results, we propose VER as a promising candidate for sensitizing S. aureus that could be helpful to combat persistent or antibiotic-resistant infections.This study was supported by Centre for the Development of Industrial Technology (CDTI), (NEO16RECOMBINA; EXP 00112635/SNEO-20161233). Work in the Laboratory of Microbial Pathogenesis is funded by the Spanish Ministry of Science, Innovation and Universities grant BIO2017-83035-R (AEI/FEDER, EU).Nature ResearchCiencias de la SaludOsasun Zientziak2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2454/39698reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglésinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BIO2017-83035-R© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/396982026-06-17T12:41:47Z
dc.title.none.fl_str_mv Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections
title Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections
spellingShingle Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections
Prieto Mariscal, Juana María
Staphylococcus aureus
GraXRS
Two component system
Verteporfin
title_short Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections
title_full Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections
title_fullStr Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections
title_full_unstemmed Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections
title_sort Inhibiting the two‑component system GraXRS with verteporfin to combat Staphylococcus aureus infections
dc.creator.none.fl_str_mv Prieto Mariscal, Juana María
Rapún Araiz, Beatriz
Gil Puig, Carmen
Penadés, José R.
Lasa Uzcudun, Íñigo
Latasa Osta, Cristina
author Prieto Mariscal, Juana María
author_facet Prieto Mariscal, Juana María
Rapún Araiz, Beatriz
Gil Puig, Carmen
Penadés, José R.
Lasa Uzcudun, Íñigo
Latasa Osta, Cristina
author_role author
author2 Rapún Araiz, Beatriz
Gil Puig, Carmen
Penadés, José R.
Lasa Uzcudun, Íñigo
Latasa Osta, Cristina
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ciencias de la Salud
Osasun Zientziak
dc.subject.none.fl_str_mv Staphylococcus aureus
GraXRS
Two component system
Verteporfin
topic Staphylococcus aureus
GraXRS
Two component system
Verteporfin
description Infections caused by Staphylococcus aureus pose a serious and sometimes fatal health issue. With the aim of exploring a novel therapeutic approach, we chose GraXRS, a Two-Component System (TCS) that determines bacterial resilience against host innate immune barriers, as an alternative target to disarm S. aureus. Following a drug repurposing methodology, and taking advantage of a singular staphylococcal strain that lacks the whole TCS machinery but the target one, we screened 1.280 offpatent FDA-approved drug for GraXRS inhibition. Reinforcing the connection between this signaling pathway and redox sensing, we found that antioxidant and redox-active molecules were capable of reducing the expression of the GraXRS regulon. Among all the compounds, verteporfin (VER) was really efficient in enhancing PMN-mediated bacterial killing, while topical administration of such drug in a murine model of surgical wound infection significantly reduced the bacterial load. Experiments relying on the chemical mimicry existing between VER and heme group suggest that redox active residue C227 of GraS participates in the inhibition exerted by this FDA-approved drug. Based on these results, we propose VER as a promising candidate for sensitizing S. aureus that could be helpful to combat persistent or antibiotic-resistant infections.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
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dc.identifier.none.fl_str_mv https://hdl.handle.net/2454/39698
url https://hdl.handle.net/2454/39698
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BIO2017-83035-R
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://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 Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
instname:Universidad Pública de Navarra
instname_str Universidad Pública de Navarra
reponame_str Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
collection Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
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