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Conversion of staphylococcal pathogenicity islands to CRISPR-carrying antibacterial agents that cure infections in
Geeta Ram1, Hope F Ross1, Richard P Novick1
1Departments of Microbiology and Medicine, New York University School of Medicine, New York, New York, USA.
Abstract:
Staphylococcus aureus and other staphylococci continue to cause life-threatening infections in both hospital and community settings. They have become increasingly resistant to antibiotics, especially β-lactams and aminoglycosides, and their infections are now, in many cases, untreatable. Here we present a non-antibiotic, non-phage method of treating staphylococcal infections by engineering of the highly mobile staphylococcal pathogenicity islands (SaPIs). We replaced the SaPIs' toxin genes with antibacterial cargos to generate antibacterial drones (ABDs) that target the infecting bacteria in the animal host, express their cargo, kill or disarm the bacteria and thus abrogate the infection. Here we have constructed ABDs with either a CRISPR-Cas9 bactericidal or a CRISPR-dCas9 virulence-blocking module. We show that both ABDs block the development of a murine subcutaneous S. aureus abscess and that the bactericidal module rescues mice given a lethal dose of S. aureus intraperitoneally.
Insights
Researchers engineered staphylococcal pathogenicity islands (SaPIs) into antibacterial drones (ABDs) to combat antibiotic-resistant Staphylococcus aureus infections. These novel ABDs effectively treat staphylococcal abscesses and lethal infections in mice.
Area of Science:
- Microbiology
- Infectious Diseases
- Biotechnology
Background:
- Staphylococcus aureus causes severe, life-threatening infections globally.
- Increasing antibiotic resistance, particularly to beta-lactams and aminoglycosides, renders many staphylococcal infections untreatable.
- Novel therapeutic strategies are urgently needed to address the challenge of resistant staphylococcal infections.
Purpose of the Study:
- To develop a non-antibiotic, non-phage therapeutic approach for staphylococcal infections.
- To engineer staphylococcal pathogenicity islands (SaPIs) into antibacterial drones (ABDs) for targeted bacterial elimination.
- To evaluate the efficacy of engineered ABDs utilizing CRISPR-Cas9 or CRISPR-dCas9 modules in preclinical models.
Main Methods:
- Engineering of staphylococcal pathogenicity islands (SaPIs) by replacing toxin genes with antibacterial payloads.
- Construction of antibacterial drones (ABDs) equipped with either a CRISPR-Cas9 bactericidal module or a CRISPR-dCas9 virulence-blocking module.
- In vivo testing of ABDs in murine models, including subcutaneous abscess development and lethal intraperitoneal infection challenges.
Main Results:
- Engineered ABDs successfully targeted and disarmed or killed infecting Staphylococcus aureus in animal hosts.
- Both bactericidal and virulence-blocking ABDs demonstrated efficacy in preventing the development of subcutaneous S. aureus abscesses in mice.
- The bactericidal ABD module was effective in rescuing mice challenged with a lethal dose of S. aureus.
Conclusions:
- Engineered staphylococcal pathogenicity islands (SaPIs) can serve as effective antibacterial drones (ABDs) for treating staphylococcal infections.
- This novel approach offers a promising alternative to conventional antibiotics for combating resistant bacterial pathogens.
- The ABD technology presents a viable strategy for developing new treatments against life-threatening staphylococcal diseases.
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