Engineering synthetic phages against pathogenic E. coli as an innovative tool for phage therapy

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SummaryA major challenge to patient safety is the hospital infections caused by Gram-negative bacteria that are resistant to antibiotics. A well-defined bacterial strain of this kind is Escherichia coli (E. coli) O18:K1:H7, which is responsible for secondary infections in burn patients, neonatal meningitis and sepsis, and acute cystitis. One of the possible solutions to this problem is the use of bacteriophages as antimicrobial agents. Bacteriophages are viruses that infect and kill bacteria. They show high specificity to their bacterial target, while having minimal side effects on the host, so they can potentially be used to treat bacterial infections in humans. However, there are still concerns for phage therapy, over the potential for immune response, rapid toxin release by the phages and difficulty of dose determination in clinical situations. Additionally, little is known about the cell biology underlying phage therapy, due to the challenges in the field, so that has been an obstacle in the rapid progress of phage therapy.The key aim of the research proposal is to engineer a model system as a tool for phage therapy consisting of 3 parts: a synthetic phage able to target a well-known pathogen, the pathogen (E.coli O18:K1:H7), and mammalian cells to test the phage-bacterium interplay mimicking the conditions of the human body. This system, with proper validation, can be used further for studies, establishing a promising proof of concept for safe phage therapy, which can treat conditions such as infection in burn wound patients, neonatal meningitis or acute cystitis, caused by the target pathogen. A combination of molecular biology, synthetic biology and microscopy methods will be enable me to achieve the objectives. The research will be undertaken in the School of Life Sciences, University of Warwick, in the lab of Professor Alfonso Jaramillo. The University of Warwick has been ranked as the 7th top institutions within the UK according to the Research Excellence Framework 2014. The School of Life Sciences was rated as world-leading (80% of its outputs were rated as world leading or internationally excellent).