We present a methodology for the design, construction, and modification of synthetic gene networks. This method emphasizes post-assembly modification of constructs based on network behavior, thus facilitating iterative design strategies and rapid tuning and repurposing of gene networks. The ease of post-construction modifications afforded by this approach and the ever-increasing repository of components within the framework will help to fast-track the development of functional genetic circuits for synthetic biology.
The increasing incidence
of antibiotic-resistant bacterial infections is creating a global
public health threat. Because conventional antibiotic drug discovery
has failed to keep pace with the rise of resistance, a growing need
exists to develop novel antibacterial methodologies. Replication-competent
bacteriophages have been utilized in a limited fashion to treat bacterial
infections. However, this approach can result in the release of harmful
endotoxins, leading to untoward side effects. Here, we engineer bacterial
phagemids to express antimicrobial peptides (AMPs) and protein toxins
that disrupt intracellular processes, leading to rapid, nonlytic bacterial
death. We show that this approach is highly modular, enabling one
to readily alter the number and type of AMPs and toxins encoded by
the phagemids. Furthermore, we demonstrate the effectiveness of engineered
phagemids in an in vivo murine peritonitis infection model. This work
shows that targeted, engineered phagemid therapy can serve as a viable,
nonantibiotic means to treat bacterial infections, while avoiding
the health issues inherent to lytic and replicative bacteriophage
use.
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