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Intracranial Subarachnoidal Route of Infection for Investigating Roles of Streptococcus suis Biofilms in Meningitis in a Mouse Infection Model
Published on: July 1, 2018
PlyNJ3: a three-domain endolysin with broad-spectrum anti-streptococcal activity and synergistic efficacy against
Jiaqi Zhao1,2, Jingju Wang1, Peizhao Han1
1MOE Joint International Research Laboratory of Animal Health and Food Safety, Risk Assessment Center of Veterinary Drug Residue and Antimicrobial Resistance, Center for Veterinary Drug Research and Evaluation, Nanjing Agricultural University, Nanjing, 210095, China.
Background:
The global spread of multidrug-resistant (MDR) bacteria prompts the exploration of innovative antimicrobial strategies. Phage lysins-peptidoglycan hydrolases known for species-specific activity and low resistance potential-offer promising alternatives to conventional antibiotics. However, their typically narrow spectrum limits broad therapeutic application. To overcome this limitation, we leveraged the wide distribution of streptococcal mobilizable prophage (SMphage) families across Streptococcus species as a strategy to discover lysins with inherent broad-spectrum potential. Within these conserved prophages, we expressed PlyNJ3, an SMphage-derived endolysin homolog identified in S. suis, and evaluated its therapeutic efficacy in infection models.
Results:
PlyNJ3 exhibited potent lytic activity against a broad panel of streptococci, including diverse S. suis clinical isolates (15 serotypes), 83.3% of S. uberis, and key strains of S. agalactiae, S. dysgalactiae, and S. pyogenes. Optimal bacteriolytic activity occurred at physiological temperature (37 °C) with dose-dependent efficacy. Electron microscopy revealed PlyNJ3-mediated cell wall perforation, cytoplasmic content release, and structural disintegration. In a murine invasive S. suis infection model, high-dose intraperitoneal PlyNJ3 (0.9 mg/head) conferred 87.5% survival, while synergism with ampicillin prolonged survival. Intramuscular administration in a murine thigh infection model enhanced bacterial clearance compared to intraperitoneal delivery. Phylogenetic and structural analysis confirmed conservation across SMphage-derived lysins, underpinning their broad streptococcal target potential.
Conclusions:
Our findings establish SMphage-derived lysins as a conserved, therapeutically valuable class of antimicrobials with inherent broad-spectrum potential across diverse streptococcal pathogens. Building on the previously demonstrated in vivo efficacy of PlySK1249 against S. dysgalactiae and S. agalactiae, we show that its structural homolog, PlyNJ3, exhibits robust therapeutic activity against S. suis infections. Together, these results validate the SMphage lysin platform for generating precision-targeted agents against specific streptococcal infections.
Insights
Novel phage lysins derived from streptococcal mobilizable prophages (SMphages) show broad-spectrum activity against diverse streptococcal pathogens. This study highlights PlyNJ3 as a promising antimicrobial agent for treating S. suis infections.
Area of Science:
- Microbiology and Infectious Diseases
- Antimicrobial Resistance
- Bacteriophage Biology
Background:
- Multidrug-resistant (MDR) bacteria necessitate novel antimicrobial strategies.
- Phage lysins offer a promising alternative to antibiotics due to their specific activity and low resistance potential.
- The narrow spectrum of traditional lysins limits their broad therapeutic use.
Purpose of the Study:
- To explore streptococcal mobilizable prophage (SMphage) families for discovering broad-spectrum lysins.
- To evaluate the therapeutic efficacy of PlyNJ3, an SMphage-derived endolysin from S. suis, in infection models.
Main Methods:
- Expression and characterization of PlyNJ3, an SMphage-derived endolysin.
- Assessment of PlyNJ3's lytic activity against various Streptococcus species and clinical isolates.
- Evaluation of PlyNJ3's efficacy in murine models of invasive S. suis infection and thigh infection.
Main Results:
- PlyNJ3 demonstrated potent lytic activity against a wide range of streptococci, including S. suis, S. uberis, S. agalactiae, S. dysgalactiae, and S. pyogenes.
- Optimal activity was observed at 37°C, with dose-dependent bacteriolysis confirmed by electron microscopy.
- In vivo studies showed significant survival rates (87.5%) with high-dose PlyNJ3 in a murine S. suis infection model, with enhanced bacterial clearance via intramuscular administration.
Conclusions:
- SMphage-derived lysins represent a conserved and therapeutically valuable class of antimicrobials with broad-spectrum potential against streptococcal pathogens.
- PlyNJ3 exhibits robust therapeutic activity against S. suis infections, complementing previous findings on PlySK1249.
- The SMphage lysin platform is validated for developing precision-targeted agents for specific streptococcal infections.
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