Engineered Bacteriophage as a Delivery Vehicle for Antibacterial Protein, SASP.
3区 · 医学
作者: James Cass ; Anne Barnard ; Heather Fairhead
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.
2009-05-01·Drug News & Perspectives
SASP gene delivery: a novel antibacterial approach
作者: Fairhead, Heather
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.