Editing the Newborn Gut Microbiome Using Engineered Phage

Srivatsan Raman of the University of Wisconsin-Madison in the U.S. will develop a platform for engineering synthetic phage - bacteria-infecting viruses - that can be easily reprogrammed to target specific bacterial species and that can be switched off to improve their safety for treating enteropathogenic diseases in newborns. Natural, so-called lytic phage have two main limitations when being considered as potential therapies: they cause death to bacteria by physically destroying them, which can release large concentrations of lethal toxins into the body, and the bacteria also evolve resistance to the phage, necessitating the identification of new phage, which is a lengthy process. They will focus on producing phage targeting enterotoxigenic Escherichia coli (ST-ETEC), which is one of the most common diarrhea-causing pathogens in infants in developing countries. They will use the Rosetta software to design thousands of proteins and test them for binding to specific bacterial receptors when incorporated into the T7 phage. They will also redesign a protein required for phage replication to make it unstable in the absence of a small molecule so it can act as an on-off safety switch in case of high toxin levels.