Constructing and Characterizing Bacteriophage Libraries for Phage Therapy of Human Infections.

Shelley B Gibson,Justin R Clark,Carmen Gu Liu,Barbara W Trautner,Heidi B Kaplan,Anthony W Maresso,Austen L Terwilliger,Sabrina I Green,Robert F Ramig,Keiko C Salazar

doi:10.3389/fmicb.2019.02537

Shelley B Gibson, Justin R Clark + Show 8 more

Open Access

https://doi.org/10.3389/fmicb.2019.02537

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Abstract

Phage therapy requires libraries of well-characterized phages. Here we describe the generation of phage libraries for three target species: Escherichia coli, Pseudomonas aeruginosa, and Enterobacter cloacae. The basic phage characteristics on the isolation host, sequence analysis, growth properties, and host range and virulence on a number of contemporary clinical isolates are presented. This information is required before phages can be added to a phage library for potential human use or sharing between laboratories for use in compassionate use protocols in humans under eIND (emergency investigational new drug). Clinical scenarios in which these phages can potentially be used are discussed. The phages presented here are currently being characterized in animal models and are available for eINDs.

Highlights

The crisis in clinical care imposed by the increasing resistance of bacterial infections to antibiotics threatens to return clinical practice to the pre-antibiotic era (Boucher et al, 2009; Centers for Disease Control [CDC], 2013; Bassetti et al, 2017; World Health Organization [WHO], 2017)
We describe the preparation of well-characterized libraries of E. coli-specific, Pseudomonas aeruginosa-specific, and Enterobacter cloacae-specific phages for use in a sur-mesure approach to phage therapy, which will result in a therapeutic that is personalized to the specific infection of the individual patient
extraintestinal pathogenic E. coli (ExPEC) are commonly associated with bacteremia and urinary tract infections, and the sequence type 131 (ST131) lineage is characterized by multi-drug resistance and its high frequency of isolation over the past 10 years

Summary

Introduction

The crisis in clinical care imposed by the increasing resistance of bacterial infections to antibiotics threatens to return clinical practice to the pre-antibiotic era (Boucher et al, 2009; Centers for Disease Control [CDC], 2013; Bassetti et al, 2017; World Health Organization [WHO], 2017). The bacterial “mutagenic tetrasect” (mutation, transformation, transduction, and conjugation) is responsible for the rapid evolution of bacteria and suggests that bacteria are so flexible in their ability to adapt that production of antibiotics by pharmaceutical companies, will never be able to keep up with the evolution of resistance against that drug. Phages can evolve to efficiently target specific bacteria and have been used to treat complex drug-resistant bacterial infections in a procedure termed phage therapy (Ghosh et al, 2018). Phage therapy has great potential as a treatment for antibiotic resistant infections, it is not without problems. Phage have a similar mutation rate to bacteria; the organisms reproduce

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