Engineering Modular Viral Scaffolds for Targeted Bacterial Population Editing

Abstract

Bacteria are central to human health and disease, but existing tools to edit microbial consortia are limited. For example, broad-spectrum antibiotics are unable to accurately manipulate bacterial communities. Bacteriophages can provide highly specific targeting of bacteria, but assembling well-defined phage cocktails solely with natural phages can be a time-, labor- and cost-intensive process. Here, we present a synthetic-biology strategy to modulate phage host ranges by engineering phage genomes in <i>Saccharomyces cerevisiae</i>. We used this technology to redirect <i>Escherichia coli</i> phage scaffolds to target pathogenic <i>Yersinia</i> and <i>Klebsiella</i> bacteria, and conversely, <i>Klebsiella</i> phage scaffolds to target <i>E. coli</i> by modular swapping of phage tail components. The synthetic phages achieved efficient killing of their new target bacteria and were used to selectively remove bacteria from multi-species bacterial communities with cocktails based on common viral scaffolds. We envision that this approach will accelerate phage-biology studies and enable new technologies for bacterial population editing.