A commentary on the development of engineered phage as therapeutics.

The use of engineered phages offers a unique opportunity to improve on wild-type (WT) phages to generate ever more successful therapeutics to combat bacterial infections. Here, we discuss how phage engineering could be used to overcome some of the technical challenges of phage therapy, and suggest some areas in which more research will be crucial to the development of further novel phage therapeutics.

Engineered Bacteriophage as a Delivery Vehicle for Antibacterial Protein, SASP.

The difficulties in developing novel classes of antibacterials is leading to a resurgence of interest in bacteriophages as therapeutic agents, and in particular engineered phages that can be optimally designed. Here, pre-clinical microbiology assessment is presented of a Staphylococcus aureus phage engineered to deliver a gene encoding an antibacterial small acid soluble spore protein (SASP) and further, rendered non-lytic to give product SASPject PT1.2. PT1.2 has been developed initially for nasal decolonisation of S. aureus, including methicillin-resistant S. aureus. Time-kill curve assays were conducted with PT1.2 against a range of staphylococcal species, and serial passaging experiments were conducted to investigate the potential for resistance to develop. SASPject PT1.2 demonstrates activity against 100% of 225 geographically diverse S. aureus isolates, exquisite specificity for S. aureus, and a rapid speed of kill. The kinetics of S. aureus/PT1.2 interaction is examined together with demonstrating that PT1.2 activity is unaffected by the presence of human serum albumin. SASPject PT1.2 shows a low propensity for resistance to develop with no consistent shift in sensitivity in S. aureus cells passaged for up to 42 days. SASPject PT1.2 shows promise as a novel first-in-class antibacterial agent and demonstrates potential for the SASPject platform.

SASP gene delivery: a novel antibacterial approach.

Antibiotic resistance is a global problem, and with bacteria having developed resistance to all approved antibacterial agents there is a growing need for innovative solutions. Phico Therapeutics has developed a new class of antibacterial agent, a platform technology called SASPject. SASPject comprises modified, disabled bacterial viruses (bacteriophages) injecting a gene encoding an antibacterial protein, SASP, into target bacteria. SASP, or Small, Acid-soluble Spore Protein(s), inactivate bacterial DNA in a non-sequence-specific manner so their activity is unaffected by DNA mutations. Selected pathogens can be targeted, avoiding the normal flora. A Staphylococcus aureus-targeted SASPject, PT1.2, developed for the nasal decolonization of S. aureus, including methicillin-resistant (MRSA) strains, is expected to complete phase I in 2009. SASPject PT1.2 shows good in vitro activity against a wide range of diverse clinical S. aureus isolates, including MRSA strains. A systemic SASPject PT1.2, and SASPjects targeted against Clostridium difficile and multidrug-resistant Gram-negative organisms are in development. The SASPject technology could represent a new paradigm in antibacterial therapeutics.

Alternatives to antibiotics-a pipeline portfolio review.

Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed. In this Review, we discuss alternatives to antibiotics, which we defined as non-compound approaches (products other than classic antibacterial agents) that target bacteria or any approaches that target the host. The most advanced approaches are antibodies, probiotics, and vaccines in phase 2 and phase 3 trials. This first wave of alternatives to antibiotics will probably best serve as adjunctive or preventive therapies, which suggests that conventional antibiotics are still needed. Funding of more than £1·5 billion is needed over 10 years to test and develop these alternatives to antibiotics. Investment needs to be partnered with translational expertise and targeted to support the validation of these approaches in phase 2 trials, which would be a catalyst for active engagement and investment by the pharmaceutical and biotechnology industry. Only a sustained, concerted, and coordinated international effort will provide the solutions needed for the future.