Engineered phage with antibacterial CRISPR-Cas selectively reduce E. coli burden in mice

Area of Science:

• Microbiology
• Bacteriophage Therapy
• Antimicrobial Resistance

Background:

• Antibiotic use disrupts the microbiome and drives antimicrobial resistance.
• Escherichia coli is a significant cause of infections, particularly in immunocompromised patients.
• Bacteriophage therapy presents a promising alternative to antibiotics for targeting specific bacterial pathogens.

Purpose of the Study:

• To develop and characterize engineered bacteriophages for broad-spectrum targeting of clinically relevant Escherichia coli strains.
• To evaluate the efficacy and safety of a novel phage combination therapy (SNIPR001) against Escherichia coli.
• To assess the potential of phage therapy in reducing bacterial load and overcoming phage resistance.

Main Methods:

• Screening of 162 wild-type phages against diverse Escherichia coli strains.
• Engineering of selected phages with modified tail fibers and CRISPR-Cas systems for enhanced targeting.
• In vitro and in vivo testing of engineered phages, including biofilm penetration and competition assays.
• Preclinical safety and efficacy studies in mouse and minipig models.

Main Results:

• Eight broad-spectrum wild-type phages were identified with desirable characteristics for engineering.
• Engineered phages demonstrated effective targeting of Escherichia coli in biofilms and reduced the emergence of phage-tolerant strains.
• A combination of four engineered phages (SNIPR001) showed superior efficacy in reducing E. coli gut load in mice compared to individual phages.
• SNIPR001 exhibited a favorable safety profile in mouse and minipig models.

Conclusions:

• Engineered bacteriophages can be developed into a targeted therapy against Escherichia coli.
• The phage combination SNIPR001 demonstrates significant potential for treating E. coli infections, especially in vulnerable patient populations.
• SNIPR001 offers a promising strategy to combat antibiotic resistance and manage E. coli-related infections.