Engineering bacteriophages for modified functionality

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As the number of cases of infections by antibiotic-resistant bacteria rapidly increases around the World, we are coming to terms with the realities and challenges of what many now call the post-antibiotics era. Among the multiple attempts to find new deterrents to bacterial infections, bacteriophages (phages) have made a resurgence. These viruses of bacteria have long been touted has potential alternatives to antibiotics (in phage therapy) but their properties - most importantly their capacity to recognize and kill specific bacteria - also make them amenable to a plethora of other applications: from biocontrol to bacterial detection, from vectors for therapeutic delivery to engineered materials. While phage-based technologies are still in their infancy, they have broad reach and can impact many aspects of our lives. The first step in developing phage-based technologies typically involves screening for phages sampled from natural environments and characterizing their properties in the hope of finding a proper fit for the application of interest. This process can be lengthy and is not always successful. Phage engineering is an alternative approach rapidly garnering interest; it consists of modifying or combining the features and properties of known phages through genetic engineering and virion functionalization. This promising strategy is currently limited by the genetic tools and methods available for phages, and the significant gaps in knowledge that still exist with regards to phage biology, genetics and regulation. In fact, for the most part, phage engineering lacks the well-established protocols and tools that have greatly enabled genetic engineering of bacteria and yeast. This critically limits the development and breadth of novel applications for phage-based technologies. The proposed program will consist of three main objectives: 1) improve the design and performance of expression cassettes in phages; 2) design structural modifications of phage virions for the improvement and control of their properties; and 3) develop a platform for the transient modification of bacteria based on engineered ghost phages. This research program will provide new knowledge on phage engineering and accelerate the development of phage-based applications in a wide variety of fields, including health, diagnostics, food security, and the environment.