Isolation of Phage Lysins That Effectively Kill Pseudomonas aeruginosa in Mouse Models of Lung and Skin Infection
| Autor: | Chad W. Euler, Anaise Hernandez, Assaf Raz, Vincent A. Fischetti, Anna Serrano |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Gram-negative bacteria
Cystic Fibrosis Lysin medicine.disease_cause complex mixtures Microbiology Mice 03 medical and health sciences chemistry.chemical_compound Drug Resistance Bacterial Endopeptidases Gram-Negative Bacteria medicine Animals Experimental Therapeutics Bacteriophages Pharmacology (medical) Skin Diseases Infectious Lung 030304 developmental biology Pharmacology 0303 health sciences biology 030306 microbiology Pseudomonas aeruginosa Enterobacter biology.organism_classification Anti-Bacterial Agents Multiple drug resistance Infectious Diseases chemistry bacteria Peptidoglycan Bacterial outer membrane Bacteria |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 63 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.00024-19 |
| Popis: | Multidrug resistance (MDR) is rapidly increasing in prevalence among isolates of the opportunistic pathogen Pseudomonas aeruginosa, leaving few treatment options. Phage lysins are cell wall hydrolases that have a demonstrated therapeutic potential against Gram-positive pathogens; however, the outer membrane of Gram-negative bacteria prevents most lysins from reaching the peptidoglycan, making them less effective as therapeutics. Nevertheless, a few lysins from Gram-negative bacterial phage can penetrate the bacterial outer membrane with the aid of an amphipathic tail found in the molecule’s termini. In this work, we took a phylogenetic approach to systematically identify those lysins from P. aeruginosa phage that would be most effective therapeutically. We isolated and performed preliminary characterization of 16 lysins and chose 2 lysins, PlyPa03 and PlyPa91, which exhibited >5-log killing activity against P. aeruginosa and other Gram-negative pathogens (particularly Klebsiella and Enterobacter). These lysins showed rapid killing kinetics and were active in the presence of high concentrations of salt and urea and under pH conditions ranging from 5.0 to 10.0. Activity was not inhibited in the presence of the pulmonary surfactant beractant (Survanta). While neither enzyme was active in 100% human serum, PlyPa91 retained activity in low serum concentrations. The lysins were effective in the treatment of a P. aeruginosa skin infection in a mouse model, and PlyPa91 protected mice in a lung infection model, making these lysins potential drug candidates for Gram-negative bacterial infections of the skin or respiratory mucosa. |
| Databáze: | OpenAIRE |
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