Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria
| Autor: | Vincent A. Fischetti, Raymond Schuch, Chad W. Euler, Ryan D. Heselpoth |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Gram-negative bacteria Lysin Colicins HL-60 Cells Peptidoglycan medicine.disease_cause Gram-Positive Bacteria Microbiology 03 medical and health sciences chemistry.chemical_compound Mice Bacteriocin Anti-Infective Agents Bacteriocins Cell Line Tumor Gram-Negative Bacteria medicine Animals Humans Pharmacology (medical) Experimental Therapeutics Bacteriophages 030304 developmental biology Pharmacology 0303 health sciences Pyocins biology 030306 microbiology Pseudomonas aeruginosa Periplasmic space biology.organism_classification Mice Inbred C57BL Infectious Diseases Bacterial Outer Membrane chemistry Periplasm bacteria Bacterial outer membrane Bacteria |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|