[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
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
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 cytotoxic domains through outer membrane protein channels. With this understanding, we developed lysocins, which are bioengineered lysin-bacteriocinfusion molecules capable of periplasmic import. In our proof of concept studies, components from the P. aeruginosa bacteriocin pyocin S2 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 P. aeruginosa death 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 towards eukaryotic cells, and protected mice from P. aeruginosa challenge in a bacteremia model. In addition to P. aeruginosa, lysocins can be constructed to target other prominent Gram-negative bacterial pathogens.
Copyright © 2019 American Society for Microbiology. All Rights Reserved.
Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Bacteriophages; Lysins; Bacteriocins; Lysocins.