Engineered endolysin-based "artilysins" to combat multidrug-resistant gram-negative pathogens

Detalhes bibliográficos
Autor(a) principal: Briers, Yves
Data de Publicação: 2014
Outros Autores: 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
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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spelling 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)
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