Engineered Phagemids for Non-Lytic, Targeted Antibacterial Technologies

Technology

This technology uses phagemids to specifically target and kill bacteria. Bacteriophages (phages) are bacteria-specific viruses that infect and lyse specific species and strains of bacteria. Phages were long ago proposed as a potential antibiotic therapy due to their exquisite specificity, however, when phage lyse their host bacteria the bacterial membrane bursts and releases endotoxins that can induce strong inflammatory reactions in patients. This technology uses a modified phage system, called phagemids, which efficiently kill bacteria without lysis and the resulting toxin release. The phagemid system uses two DNA vectors, one that expresses antimicrobial peptides (AMPs), and a second that specifically packages the AMP vector. When transformed into a strain of packaging bacteria, these vectors produce large amounts of replication-defective phage that can be purified and used as an antibiotic. This phagemid technology has several important improvements over existing technologies. Firstly, the phagemids are replication-deficient and do not result in propagation of more phage, which eliminates the potential for unregulated phage evolution. Secondly, the non-lytic nature of the phagemids reduces toxicity due to bacterial bursting and reduces the formation of bacteriophage resistance. As a proof of principle, the inventors demonstrated that the AMP phagemids were highly effective in treating a mouse in vivo model of E.coli peritonitis.

Problem Addressed

Bacterial antibiotic resistance is a major health crisis that results in 23,000 deaths and $55 billion in healthcare expenditures every year in the US alone. The rate of bacterial acquisition of antibiotic resistance outpaces the rate of development of new antibiotics; therefore, there is an urgent need to develop new antibiotic therapies. This technology is a novel, highly effective antibiotic with potential therapeutic applications.

Advantages

• Modular vector system allows rapid customization of phage characteristics and customizable choice of antimicrobial peptides
• Non-lytic bacterial killing reduces toxicity
• Non-replicative phage eliminates unregulated evolution
• Reduces the formation of bacterial resistance
• Demonstrated in vivo effectiveness in a mouse model of peritonitis

Publications

Krom, Russell J., et al. "Engineered Phagemids for Nonlytic, Targeted Antibacterial Therapies." Nano Letters 15, no. 7 (2015): 4808-4813. doi: 10.1021/acs.nanolett.5b01943.