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

Autor:	Heselpoth RD; Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA rheselpoth@rockefeller.edu., Euler CW; Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.; Department of Medical Laboratory Sciences, Hunter College, CUNY, New York, New York, USA.; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA., Schuch R; ContraFect Corporation, Yonkers, New York, USA., Fischetti VA; Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2019 May 24; Vol. 63 (6). Date of Electronic Publication: 2019 May 24 (Print Publication: 2019).
DOI:	10.1128/AAC.00342-19
Abstrakt:	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 lys in-bacteri ocin 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. (Copyright © 2019 American Society for Microbiology.)
Databáze:	MEDLINE
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