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Editor's Pick Experimental Therapeutics

Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria

Ryan D. Heselpoth, Chad W. Euler, Raymond Schuch, Vincent A. Fischetti
Ryan D. Heselpoth
aLaboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA
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Chad W. Euler
aLaboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA
bDepartment of Medical Laboratory Sciences, Hunter College, CUNY, New York, New York, USA
cDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA
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Raymond Schuch
dContraFect Corporation, Yonkers, New York, USA
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Vincent A. Fischetti
aLaboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA
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DOI: 10.1128/AAC.00342-19
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ABSTRACT

The prevalence of multidrug-resistant Pseudomonas aeruginosa has stimulated development of alternative therapeutics. Bacteriophage peptidoglycan hydrolases, termed lysins, represent an emerging antimicrobial option for targeting Gram-positive bacteria. However, lysins against Gram-negatives are generally deterred by the outer membrane and their inability to work in serum. One solution involves exploiting evolved delivery systems used by colicin-like bacteriocins (e.g., S-type pyocins of P. aeruginosa) to translocate through the outer membrane. Following surface receptor binding, colicin-like bacteriocins form Tol- or TonB-dependent translocons to actively import bactericidal domains through outer membrane protein channels. With this understanding, we developed lysocins, which are bioengineered lysin-bacteriocin fusion molecules capable of periplasmic import. In our proof-of-concept studies, components from the P. aeruginosa bacteriocin pyocin S2 (PyS2) responsible for surface receptor binding and outer membrane translocation were fused to the GN4 lysin to generate the PyS2-GN4 lysocin. PyS2-GN4 delivered the GN4 lysin to the periplasm to induce peptidoglycan cleavage and log-fold killing of P. aeruginosa with minimal endotoxin release. While displaying narrow-spectrum antipseudomonal activity in human serum, PyS2-GN4 also efficiently disrupted biofilms, outperformed standard-of-care antibiotics, exhibited no cytotoxicity toward eukaryotic cells, and protected mice from P. aeruginosa challenge in a bacteremia model. In addition to targeting P. aeruginosa, lysocins can be constructed to target other prominent Gram-negative bacterial pathogens.

FOOTNOTES

    • Received 14 February 2019.
    • Returned for modification 23 March 2019.
    • Accepted 3 April 2019.
    • Accepted manuscript posted online 8 April 2019.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00342-19.

  • Copyright © 2019 American Society for Microbiology.

All Rights Reserved.

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Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria
Ryan D. Heselpoth, Chad W. Euler, Raymond Schuch, Vincent A. Fischetti
Antimicrobial Agents and Chemotherapy May 2019, 63 (6) e00342-19; DOI: 10.1128/AAC.00342-19

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Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria
Ryan D. Heselpoth, Chad W. Euler, Raymond Schuch, Vincent A. Fischetti
Antimicrobial Agents and Chemotherapy May 2019, 63 (6) e00342-19; DOI: 10.1128/AAC.00342-19
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KEYWORDS

ESKAPE
Pseudomonas aeruginosa
antibiotic resistance
antimicrobial
endolysin
lysin
lysocin
peptidoglycan hydrolase
protein delivery

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