Engineered Bacteriophage as a Delivery Vehicle for Antibacterial Protein, SASP

Abstract

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.