Conversion of staphylococcal pathogenicity islands to CRISPR-Cas9-based antibacterial drones that cure staph infections in mice

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)(4). 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. As proof of concept, 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.