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Monomodular Pseudomonas aeruginosa phage JG004 lysozyme (Pae87) contains a bacterial surface-active antimicrobial peptide-like region and a possible substrate-binding subdomain

View ORCID ProfileRoberto Vázquez, Mateo Seoane-Blanco, Virginia Rivero-Buceta, Susana Ruiz, Mark J. van Raaij, Pedro García
doi: https://doi.org/10.1101/2022.01.10.475687
Roberto Vázquez
aMicrobial and Plant Biotechnology Department, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid (Spain)
bCentro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid (Spain)
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  • ORCID record for Roberto Vázquez
Mateo Seoane-Blanco
cDepartment of Macromolecular Structure, Centro Nacional de Biotecnología (CNB-CSIC), Madrid (Spain)
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Virginia Rivero-Buceta
aMicrobial and Plant Biotechnology Department, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid (Spain)
dInterdisciplinary Platform for Sustainable Plastics towards a Circular Economy (SusPlast-CSIC), Madrid (Spain)
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Susana Ruiz
aMicrobial and Plant Biotechnology Department, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid (Spain)
bCentro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid (Spain)
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Mark J. van Raaij
cDepartment of Macromolecular Structure, Centro Nacional de Biotecnología (CNB-CSIC), Madrid (Spain)
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Pedro García
aMicrobial and Plant Biotechnology Department, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid (Spain)
bCentro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid (Spain)
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  • For correspondence: pgarcia@cib.csic.es
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Abstract

Phage lysins are a source of novel antimicrobials to tackle the bacterial antibiotic resistance crisis. The engineering of phage lysins is being explored as a game-changing technological strategy for introducing a more precise approach in the way we apply antimicrobial therapy. Such engineering efforts will benefit from a better understanding of lysin structure and function. In this work, the antimicrobial activity of the endolysin from Pseudomonas aeruginosa phage JG004, termed Pae87, has been characterized. This lysin had been previously identified as an antimicrobial agent candidate, able to interact with the Gram-negative surface and disrupt it. Further evidence is hereby provided on this matter, based on a structural and biochemical study. A high-resolution crystal structure of Pae87 complexed with a peptidoglycan fragment showed a separate substrate-binding region within the catalytic domain, 18 Å away from the catalytic site and located at the opposite side of the lysin molecule. This substrate binding region was conserved among phylogenetically related lysins lacking an additional cell wall binding domain, but not among those containing such a module. Two glutamic acids were identified as relevant for the peptidoglycan degradation activity, although Pae87 antimicrobial activity was seemingly unrelated to it. In contrast, an antimicrobial peptide-like region within Pae87 C-terminus, named P87, was found to be able to actively disturb the outer membrane and have antibacterial activity by itself. Therefore, we propose an antimicrobial mechanism for Pae87 in which the P87 peptide plays the role of binding to the outer membrane and disrupting the cell wall function, either with or without the participation of Pae87 catalytic activity.

Synopsis The structure of the monomodular Pseudomonas aeruginosa bacteriophage JG004 lysin Pae87 is presented and investigated in relationship with its function repurposed as an antimicrobial agent. The structure with its peptidoglycan ligand revealed a possible cell wall binding region. A C-terminal antimicrobial peptide-like region is shown to be important for disrupting the bacterial cell wall.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 10, 2022.
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Monomodular Pseudomonas aeruginosa phage JG004 lysozyme (Pae87) contains a bacterial surface-active antimicrobial peptide-like region and a possible substrate-binding subdomain
Roberto Vázquez, Mateo Seoane-Blanco, Virginia Rivero-Buceta, Susana Ruiz, Mark J. van Raaij, Pedro García
bioRxiv 2022.01.10.475687; doi: https://doi.org/10.1101/2022.01.10.475687
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Monomodular Pseudomonas aeruginosa phage JG004 lysozyme (Pae87) contains a bacterial surface-active antimicrobial peptide-like region and a possible substrate-binding subdomain
Roberto Vázquez, Mateo Seoane-Blanco, Virginia Rivero-Buceta, Susana Ruiz, Mark J. van Raaij, Pedro García
bioRxiv 2022.01.10.475687; doi: https://doi.org/10.1101/2022.01.10.475687

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