Objectives: Community-acquired pneumonia is a very common infectious disease associated with significant morbidity and mortality. Streptococcus pneumoniae is the predominant pathogen in this disease, and pneumococcal resistance to multiple antibiotics is increasing. The recently purified bacteriophage endolysin Cpl-1 rapidly and specifically kills pneumococci on contact. The aim of this study was to determine the therapeutic potential of Cpl-1 in a mouse model of severe pneumococcal pneumonia.
Design: Controlled, in vivo laboratory study.
Subjects: Female C57/Bl6 mice, 8-12 weeks old.
Interventions: Mice were transnasally infected with pneumococci and therapeutically treated with Cpl-1 or amoxicillin by intraperitoneal injections starting 24 or 48 hours after infection.
Measurements And Main Results: Judged from clinical appearance, decreased body weight, reduced dynamic lung compliance and Pao2/Fio2 ratio, and morphologic changes in the lungs, mice suffered from severe pneumonia at the onset of therapy. When treatment was commenced 24 hours after infection, 100% Cpl-1-treated and 86% amoxicillin-treated mice survived otherwise fatal pneumonia and showed rapid recovery. When treatment was started 48 hours after infection, mice had developed bacteremia, and three of seven (42%) Cpl-1-treated and five of seven (71%) amoxicillin-treated animals survived. Cpl-1 dramatically reduced pulmonary bacterial counts, and prevented bacteremia, systemic hypotension, and lactate increase when treatment commenced at 24 hours. In vivo, treatment with Cpl-1 or amoxicillin effectively reduced counts of penicillin-susceptible pneumococci. The inflammatory response in Cpl-1-and amoxicillin-treated mice was lower than in untreated mice, as determined by multiplex cytokine assay of lung and blood samples. In human epithelial cell cultures, lysed bacteria evoked less proinflammatory cytokine release and cell death, as compared with viable bacteria.
Conclusions: Cpl-1 may provide a new therapeutic option in the treatment of pneumococcal pneumonia.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1097/CCM.0b013e31819586a6 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
SP-CHAP, an endolysin with enhanced activity against biofilm pneumococci and nasopharyngeal colonization.
mBio
April 2024
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland, USA.
Unlabelled: (), a Gram-positive bacterium, is responsible for causing a wide variety of invasive infections. The emergence of multi-drug antibiotic resistance has prompted the search for antimicrobial alternatives. Phage-derived peptidoglycan hydrolases, known as endolysins, are an attractive alternative.
View Article and Find Full Text PDFSynthetic mRNA delivered to human cells leads to expression of Cpl-1 bacteriophage-endolysin with activity against .
Mol Ther Nucleic Acids
March 2024
Institute of Medical Microbiology, Virology and Hygiene, University Medicine Rostock, Rostock, Germany.
Endolysins are bacteriophage-encoded hydrolases that show high antibacterial activity and a narrow substrate spectrum. We hypothesize that an mRNA-based approach to endolysin therapy can overcome some challenges of conventional endolysin therapy, namely organ targeting and bioavailability. We show that synthetic mRNA applied to three human cell lines (HEK293T, A549, HepG2 cells) leads to expression and cytosolic accumulation of the Cpl-1 endolysin with activity against Addition of a human lysozyme signal peptide sequence translocates the Cpl-1 to the endoplasmic reticulum leading to secretion (hlySP-sCpl-1).
View Article and Find Full Text PDFImmunogenic epitope scanning in bacteriolytic enzymes Pal and Cpl-1 and engineering Pal to escape antibody responses.
Front Immunol
October 2023
Laboratory of Phage Molecular Biology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
Bacteriolytic enzymes are promising antibacterial agents, but they can cause a typical immune response . In this study, we used a targeted modification method for two antibacterial endolysins, Pal and Cpl-1. We identified the key immunogenic amino acids, and designed and tested new, bacteriolytic variants with altered immunogenicity.
View Article and Find Full Text PDFUnderstanding the Molecular Basis for Homodimer Formation of the Pneumococcal Endolysin Cpl-1.
ACS Infect Dis
May 2023
Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, USA.
The rise of multi-drug-resistant bacteria that cannot be treated with traditional antibiotics has prompted the search for alternatives to combat bacterial infections. Endolysins, which are bacteriophage-derived peptidoglycan hydrolases, are attractive tools in this fight. Several studies have already demonstrated the efficacy of endolysins in targeting bacterial infections.
View Article and Find Full Text PDFBacteriophage endolysin powders for inhaled delivery against pulmonary infections.
Int J Pharm
March 2023
Advanced Drug Delivery Group, School of Pharmacy, University of Sydney, Sydney, NSW, Australia. Electronic address:
Endolysins are bacteriophage-encoded enzymatic proteins that have great potential to treat multidrug-resistant bacterial infections. Bacteriophage endolysins Cpl-1 and ClyJ-3 have shown promising antimicrobial activity against Streptococcus pneumoniae, which causes pneumonia in humans. This is the first study to investigate the feasibility of spray-dried endolysins Cpl-1 and ClyJ-3 with excipients to produce inhalable powders.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!