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Pathways to synthetic bacteriophages for phage therapy: Do tRNAs control host-range and virulence?

Primary Supervisor: Dr Richard Puxty, School of Life Sciences

Secondary supervisor: Professor Elizabeth Wellington; Professor Martha Clokie (University of Leicester)

PhD project title: Pathways to synthetic bacteriophages for phage therapy: Do tRNAs control host-range and virulence?

University of Registration: University of Warwick

Project outline:

Viruses of bacteria (bacteriophages) are a powerful approach for treating multi-drug resistant bacterial infections1. Recent use of bacteriophage as drugs of last resort suggests they are effective in treating morbidity associated with chronic Mycobacterium infections2. Concurrently, using synthetic biology approaches3, 4, bacteriophages can be engineered to target specific hosts and with increases in virulence. To maximise the exploitation of both bacteriophage therapy and bacteriophage genetic engineering, a mechanistic understanding of the factors controlling host-range and virulence is required. This knowledge will enable the construction of the next generation of therapeutics, involving synthetic bacteriophage with known host ranges, improved virulence and the ability to avoid host spontaneous resistance.

We have preliminary evidence for a radical mechanism controlling both host-range and virulence involving bacteriophage encoded tRNA molecules. This PhD project will directly test whether tRNAs encoded by mycobacteriophages contribute to host-range and virulence. To achieve this you will exploit synthetic biology techniques to generate unmarked mutations in bacteriophage genomes (e.g. through CRISPR/Cas) and combine these with host-range and virulence assays. You will be part of a growing team of researchers at both Warwick and Leicester operating at the forefront of bacteriophage genetics and phage therapy.

References:

  1. Lin et al., 2107. Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World J Gastrointest Pharmacol Ther. 8(3), 162–173.
  2. Dedrick et al., 2019. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nature Medicine, 25, 730–733.
  3. Marinelli et al., 2008. BRED: A simple and powerful tool for constructing mutant and recombinant bacteriophage genomes. PLoS ONE 3 (12), e3957.
  4. Tao et al., 2017. Engineering of Bacteriophage T4 Genome Using CRISPR-Cas9. ACS Synth. Biol., 6, 10, 1952-1961.

BBSRC Strategic Research Priority: Understanding the rule of life: Microbiology

Techniques that will be undertaken during the project:

  • Molecular cloning
  • CRISPR/Cas and BRED gene knockout systems
  • Polysome profiling
  • Viral host-range assays
  • Bacteriophage virulence assays
  • Confocal microscopy
  • Genome mining
  • Bioinformatics

Contact: Dr Richard Puxty, University of Warwick