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Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur

Pseudomonas aeruginosa is a priority pathogen for the development of new antibiotics, particularly because multi-drug-resistant strains of this bacterium cause serious nosocomial infections and are the leading cause of death in cystic fibrosis patients. Pyocins, bacteriocins of P. aeruginosa, are po...

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Autores principales: Atanaskovic, Iva, Mosbahi, Khedidja, Sharp, Connor, Housden, Nicholas G., Kaminska, Renata, Walker, Daniel, Kleanthous, Colin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322526/
https://www.ncbi.nlm.nih.gov/pubmed/32339530
http://dx.doi.org/10.1016/j.jmb.2020.04.020
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author Atanaskovic, Iva
Mosbahi, Khedidja
Sharp, Connor
Housden, Nicholas G.
Kaminska, Renata
Walker, Daniel
Kleanthous, Colin
author_facet Atanaskovic, Iva
Mosbahi, Khedidja
Sharp, Connor
Housden, Nicholas G.
Kaminska, Renata
Walker, Daniel
Kleanthous, Colin
author_sort Atanaskovic, Iva
collection PubMed
description Pseudomonas aeruginosa is a priority pathogen for the development of new antibiotics, particularly because multi-drug-resistant strains of this bacterium cause serious nosocomial infections and are the leading cause of death in cystic fibrosis patients. Pyocins, bacteriocins of P. aeruginosa, are potent and diverse protein antibiotics that are deployed during bacterial competition. Pyocins are produced by more than 90% of P. aeruginosa strains and may have utility as last resort antibiotics against this bacterium. In this study, we explore the antimicrobial activity of a newly discovered pyocin called pyocin G (PyoG). We demonstrate that PyoG has broad killing activity against a collection of clinical P. aeruginosa isolates and is active in a Galleria mellonella infection model. We go on to identify cell envelope proteins that are necessary for the import of PyoG and its killing activity. PyoG recognizes bacterial cells by binding to Hur, an outer-membrane TonB-dependent transporter. Both pyocin and Hur interact with TonB1, which in complex with ExbB–ExbD links the proton motive force generated across the inner membrane with energy-dependent pyocin translocation across the outer membrane. Inner-membrane translocation of PyoG is dependent on the conserved inner-membrane AAA + ATPase/protease, FtsH. We also report a functional exploration of the PyoG receptor. We demonstrate that Hur can bind to hemin in vitro and that this interaction is blocked by PyoG, confirming the role of Hur in hemin acquisition.
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spelling pubmed-73225262020-06-30 Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur Atanaskovic, Iva Mosbahi, Khedidja Sharp, Connor Housden, Nicholas G. Kaminska, Renata Walker, Daniel Kleanthous, Colin J Mol Biol Article Pseudomonas aeruginosa is a priority pathogen for the development of new antibiotics, particularly because multi-drug-resistant strains of this bacterium cause serious nosocomial infections and are the leading cause of death in cystic fibrosis patients. Pyocins, bacteriocins of P. aeruginosa, are potent and diverse protein antibiotics that are deployed during bacterial competition. Pyocins are produced by more than 90% of P. aeruginosa strains and may have utility as last resort antibiotics against this bacterium. In this study, we explore the antimicrobial activity of a newly discovered pyocin called pyocin G (PyoG). We demonstrate that PyoG has broad killing activity against a collection of clinical P. aeruginosa isolates and is active in a Galleria mellonella infection model. We go on to identify cell envelope proteins that are necessary for the import of PyoG and its killing activity. PyoG recognizes bacterial cells by binding to Hur, an outer-membrane TonB-dependent transporter. Both pyocin and Hur interact with TonB1, which in complex with ExbB–ExbD links the proton motive force generated across the inner membrane with energy-dependent pyocin translocation across the outer membrane. Inner-membrane translocation of PyoG is dependent on the conserved inner-membrane AAA + ATPase/protease, FtsH. We also report a functional exploration of the PyoG receptor. We demonstrate that Hur can bind to hemin in vitro and that this interaction is blocked by PyoG, confirming the role of Hur in hemin acquisition. Elsevier 2020-06-12 /pmc/articles/PMC7322526/ /pubmed/32339530 http://dx.doi.org/10.1016/j.jmb.2020.04.020 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Atanaskovic, Iva
Mosbahi, Khedidja
Sharp, Connor
Housden, Nicholas G.
Kaminska, Renata
Walker, Daniel
Kleanthous, Colin
Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur
title Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur
title_full Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur
title_fullStr Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur
title_full_unstemmed Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur
title_short Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur
title_sort targeted killing of pseudomonas aeruginosa by pyocin g occurs via the hemin transporter hur
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322526/
https://www.ncbi.nlm.nih.gov/pubmed/32339530
http://dx.doi.org/10.1016/j.jmb.2020.04.020
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