An Adaptive Framework to Synthesize and Reconfigure Bacterial Viruses (Phages) to Counter Antibiotic Resistance

Overview

The growing antibiotic resistance crisis has revived interest in phage therapy (the use of viruses that infect and lyse bacteria) to treat drug-resistant pathogenic infections. Despite its promise, current phage therapy development faces significant challenges in scalability and accessibility. Since phages are highly specific to their bacterial hosts, it is difficult for a developed phage therapy to maintain treatment efficacy across various and evolving strains of the same pathogen. This necessitates a continuous search for and development of new phages, which is highly time- and resource-intensive. Moreover, phage genomes have evolved to be highly compressed; that is, the same stretch of sequence encodes multiple proteins in different reading frames, which severely limits the possibilities for phage genome engineering and reconfiguration.
To attain the breakthrough capability to facilitate phage therapy development against any antibiotic-resistant pathogen, this proposal aims to develop an adaptive framework to rapidly synthesize and reconfigure synthetic phages. Specifically, we will decompress phage genomes into physically distinct open reading frames using in vitro genome assembly and synthesize decompressed phages using the E. coli cell-free system. This innovative approach will create modular phage genomes compatible with interchangeable parts and a generalizable expression platform for on-demand phage synthesis.

Current Participants:

Funding

Supported by the NIH MOSAIC Pathway to Independence Career Transition Award (K99/R00).

Agency: NIBIB
Grant #: K99EB036553
K99 phase (mentored): California Institute of Technology
R00 phase (independent): Rice University
Start date: December 1st, 2024
End date: November 30th, 2029
Reporting: Annual