Engineered bacteriophage as a platform to deliver nucleic acid based therapeutics to bacteria to disperse biofilms in implant-associated infections such as prosthetic joint infections

Period of Performance: 07/01/2016 - 12/31/2016

$264K

Phase 1 SBIR

Recipient Firm

Enbiotix, Inc.
BOSTON, MA 02118
Principal Investigator

Abstract

Abstract Bacteriophages are viruses that specifically and solely infect bacteria and are a natural platformdelivery system of genetic information, encoded by nucleic acids, to bacteria. Lytic bacteriophages do notintegrate their DNA into the bacterial chromosome, but replicate independently and ultimately kill their hostbacteria. In the early 1900's bacteriophages were used to fight infections in humans, but largely fell to thewayside after the discovery of antibiotics in the 1920's. Only in Eastern Europe and the former SovietRepublics are bacteriophages still considered as effective therapeutic agents. With the antibioticarmamentarium currently challenged by the combination of increasing antibiotic resistance and a dearth of newinvestment and discovery in new classes of antibiotics, natural bacteriophage therapy is experiencing arenaissance. Along with this renaissance in bacteriophage therapy, advances in systems and synthetic biologynow enable exquisite engineering of bacteriophage genomes to introduce nucleic acid therapeutics to alter thephysiology, pathogenicity, virulence and antibiotic sensitivity of targeted bacterial species. Bacteriophage canthus be designed to deliver genetic payloads to achieve specific desired effects, such as enhancing antibiotickilling by genetic repression of DNA repair mechanisms, the self-generation of antimicrobial peptides andproteins and expression of enzymes to degrade bacterial biofilms. Biofilm-associated infections are particularly difficult to treat due to the physical and physiologicalbarriers biofilms pose to antimicrobial agents and host defenses. Biofilms are central to the pathogenesis ofmany serious clinical infections, and often colonize foreign-body surfaces, such as in prosthetic joint infections(PJI). The annual cost of PJI to US hospitals in 2009 was $566M and is projected to increase to $1.62B by2020. Much of this cost is for surgical replacement of infected prostheses due to the failure of medicaltreatment. Failure of medical treatment is most problematic in device infections caused by S. aureus, due toits virulence and rapid biofilm formation. This proposal seeks to improve medical treatment for PJI, caused byS. aureus, by utilizing engineered bacteriophage to deliver nucleic acid therapeutics to the bacteria encodingbiofilm-degrading enzymes to disperse the protective biofilm. Removal of the biofilm will reduce the inherenttolerance of bacteria to antimicrobial therapy, improve medical treatment outcomes and thereby reducesurgical intervention, prosthesis replacement and the associated health costs and patient burden.