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Preventing therapeutic failure during phage therapy

Westmead Institute for Medical Research

Grant:
  • Early-Mid Career Fellowship
Date Funded:
  • 17 May, 2021
Chief Investigator/s:
  • Professor Jon Iredell

Research intent

Preventing clinical failure in phage therapy by recognising and re-engineering pseudolysogenic phages.

What is the issue?

This research will bridge a knowledge gap in the biology of the most commonly prescribed (T4-specific) phages, which we have shown for the first time to have capacity to hibernate (instead of kill) in bacteria in growth stages that are routinely expected in clinical conditions, including bacteria in biofilm and L-forms, for which phage therapy is most commonly proposed.

What does the research aim to do and how?

We will build on our experience in human phage therapy to prevent therapeutic failure, firstly by identifying problematic phages and then by genetically engineering out the region in the genome that is responsible for in vivo pseudolysogeny (hibernation).

Finally, we will develop license and test optimal phage cocktails with high lytic potential and therefore most likely to produce optimal therapeutic outcomes.

  1. Identify genes/modules that drive pseudolysogeny (e.g.by TraDIS) by in vitro, testing against important target strains in the presence and absence of high-dose carbapenem antibiotics.
  2. Genetically modify (e.g. by induced mutagenesis and homologous recombination) selected high-value phage to remove their pseudolysogenic propensity and thereby create an optimised phage with activity against all stages of the bacterial life cycle.
  3. Generate phage cocktails which do not have an intrinsic propensity to enter pseudolysogeny and encourage development of resistance in vivo.