Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/31928 |
Resumo: | The global threat to public health posed by emerging multidrug-resistant bacteria in the past few years necessitates the development of novel approaches to combat bacterial infections. Endolysins encoded by bacterial viruses (or phages) represent one promising avenue of investigation. These enzyme-based antibacterials efficiently kill Gram-positive bacteria upon contact by specific cell wall hydrolysis. However, a major hurdle in their exploitation as antibacterials against Gram-negative pathogens is the impermeable lipopolysaccharide layer surrounding their cell wall. Therefore, we developed and optimized an approach to engineer these enzymes as outer membrane-penetrating endolysins (Artilysins), rendering them highly bactericidal against Gram-negative pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. Artilysins combining a polycationic nonapeptide and a modular endolysin are able to kill these (multidrug-resistant) strains in vitro with a 4 to 5 log reduction within 30 min. We show that the activity of Artilysins can be further enhanced by the presence of a linker of increasing length between the peptide and endolysin or by a combination of both polycationic and hydrophobic/amphipathic peptides. Time-lapse microscopy confirmed the mode of action of polycationic Artilysins, showing that they pass the outer membrane to degrade the peptidoglycan with subsequent cell lysis. Artilysins are effective in vitro (human keratinocytes) and in vivo (Caenorhabditis elegans). |
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Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogensScience & TechnologyThe global threat to public health posed by emerging multidrug-resistant bacteria in the past few years necessitates the development of novel approaches to combat bacterial infections. Endolysins encoded by bacterial viruses (or phages) represent one promising avenue of investigation. These enzyme-based antibacterials efficiently kill Gram-positive bacteria upon contact by specific cell wall hydrolysis. However, a major hurdle in their exploitation as antibacterials against Gram-negative pathogens is the impermeable lipopolysaccharide layer surrounding their cell wall. Therefore, we developed and optimized an approach to engineer these enzymes as outer membrane-penetrating endolysins (Artilysins), rendering them highly bactericidal against Gram-negative pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. Artilysins combining a polycationic nonapeptide and a modular endolysin are able to kill these (multidrug-resistant) strains in vitro with a 4 to 5 log reduction within 30 min. We show that the activity of Artilysins can be further enhanced by the presence of a linker of increasing length between the peptide and endolysin or by a combination of both polycationic and hydrophobic/amphipathic peptides. Time-lapse microscopy confirmed the mode of action of polycationic Artilysins, showing that they pass the outer membrane to degrade the peptidoglycan with subsequent cell lysis. Artilysins are effective in vitro (human keratinocytes) and in vivo (Caenorhabditis elegans).M.W. held a predoctoral fellowship of the "Instituut voor aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen" (IWT Flanders). Y.B. and M. W. were supported by IWT Flanders and Y.B. by a postdoctoral fellowship of the "Bijzonder Onderzoeksfonds-KU Leuven." S. M. is an employee of Lisando GmbH. R. L. acts as scientific adviser to Lisando GmbH.American Society For MicrobiologyUniversidade do MinhoBriers, YvesWalmagh, MaartenVan Puyenbroeck, VictorCornelissen, AnneleenCenens, WilliamAertsen, AbramOliveira, HugoAzeredo, JoanaVerween, GuntherPirnay, Jean-PaulMiller, StefanVolckaert, GuidoLavigne, Rob20142014-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/31928engBriers, Y.; Walmagh, M.; Van Puyenbroeck, V.; Cornelissen, A.; Cenens, W.; Aertsen, A.; Oliveira, Hugo; Azeredo, Joana; Verween, G.; Pirnay, J. P.; Miller, S.; Volckaert, G.; Lavigne, R., Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens. mBio, 5(4), e01379-14, 20142161-21292150-751110.1128/mBio.01379-1424987094http://mbio.asm.org/info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-10T01:18:42Zoai:repositorium.sdum.uminho.pt:1822/31928Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:47:00.672562Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens |
title |
Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens |
spellingShingle |
Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens Briers, Yves Science & Technology |
title_short |
Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens |
title_full |
Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens |
title_fullStr |
Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens |
title_full_unstemmed |
Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens |
title_sort |
Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens |
author |
Briers, Yves |
author_facet |
Briers, Yves Walmagh, Maarten Van Puyenbroeck, Victor Cornelissen, Anneleen Cenens, William Aertsen, Abram Oliveira, Hugo Azeredo, Joana Verween, Gunther Pirnay, Jean-Paul Miller, Stefan Volckaert, Guido Lavigne, Rob |
author_role |
author |
author2 |
Walmagh, Maarten Van Puyenbroeck, Victor Cornelissen, Anneleen Cenens, William Aertsen, Abram Oliveira, Hugo Azeredo, Joana Verween, Gunther Pirnay, Jean-Paul Miller, Stefan Volckaert, Guido Lavigne, Rob |
author2_role |
author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Briers, Yves Walmagh, Maarten Van Puyenbroeck, Victor Cornelissen, Anneleen Cenens, William Aertsen, Abram Oliveira, Hugo Azeredo, Joana Verween, Gunther Pirnay, Jean-Paul Miller, Stefan Volckaert, Guido Lavigne, Rob |
dc.subject.por.fl_str_mv |
Science & Technology |
topic |
Science & Technology |
description |
The global threat to public health posed by emerging multidrug-resistant bacteria in the past few years necessitates the development of novel approaches to combat bacterial infections. Endolysins encoded by bacterial viruses (or phages) represent one promising avenue of investigation. These enzyme-based antibacterials efficiently kill Gram-positive bacteria upon contact by specific cell wall hydrolysis. However, a major hurdle in their exploitation as antibacterials against Gram-negative pathogens is the impermeable lipopolysaccharide layer surrounding their cell wall. Therefore, we developed and optimized an approach to engineer these enzymes as outer membrane-penetrating endolysins (Artilysins), rendering them highly bactericidal against Gram-negative pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. Artilysins combining a polycationic nonapeptide and a modular endolysin are able to kill these (multidrug-resistant) strains in vitro with a 4 to 5 log reduction within 30 min. We show that the activity of Artilysins can be further enhanced by the presence of a linker of increasing length between the peptide and endolysin or by a combination of both polycationic and hydrophobic/amphipathic peptides. Time-lapse microscopy confirmed the mode of action of polycationic Artilysins, showing that they pass the outer membrane to degrade the peptidoglycan with subsequent cell lysis. Artilysins are effective in vitro (human keratinocytes) and in vivo (Caenorhabditis elegans). |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014 2014-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/1822/31928 |
url |
https://hdl.handle.net/1822/31928 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Briers, Y.; Walmagh, M.; Van Puyenbroeck, V.; Cornelissen, A.; Cenens, W.; Aertsen, A.; Oliveira, Hugo; Azeredo, Joana; Verween, G.; Pirnay, J. P.; Miller, S.; Volckaert, G.; Lavigne, R., Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens. mBio, 5(4), e01379-14, 2014 2161-2129 2150-7511 10.1128/mBio.01379-14 24987094 http://mbio.asm.org/ |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
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:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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