Coevolutionary phage training leads to greater bacterial suppression and delays the evolution of phage resistance

Joshua M. Borin, Sarit Avrani, Jeffrey E. Barrick, Katherine L. Petrie, Justin R. Meyer

Research output: Contribution to journalArticlepeer-review

Abstract

The evolution of antibiotic-resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria's capacity to evolve resistance may debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many suggest leveraging phages' ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that in vitro, λtrn, a phage trained for 28 d, suppressed bacteria ∼1,000-fold for three to eight times longer than its untrained ancestor. Prolonged suppression was due to a delay in the evolution of resistance caused by several factors. Mutations that confer resistance to λtrn are ∼100× less common, and while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to λtrn. Mutations that confer resistance to λtrn are more costly than mutations for untrained phage resistance. Furthermore, when resistance does evolve, λtrn is better able to suppress these forms of resistance. One way that λtrn improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This transfer of information from the host genome is an unexpected but highly efficient mode of training phage. Lastly, we found that many other independently trained λ phages were able to suppress bacterial populations, supporting the important role training could play during phage therapeutic development.

Original languageEnglish
Article numbere2104592118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number23
DOIs
StatePublished - 8 Jun 2021

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank members Sarah Medina and Elijah Horwitz of the J.R.M. laboratory for productive discussions and feedback on this study. This work was supported by the United States–Israel Binational Science Foundation (Grant 2017056), the NIH Grant R01 (Grant GM088344), the Chris Wills Endowed Graduate Student Research Award, and the NIH Cell and Molecular Genetic Training Program (Grant T32GM007240).

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Keywords

  • Coevolution
  • Evolution
  • Phage therapy
  • Phage training
  • Resistance

ASJC Scopus subject areas

  • General

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