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Bacteriophages as Therapeutic Delivery Vehicles

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (30 July 2021) | Viewed by 55079

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Special Issue Editors

Prof. Dr. Paul Hyman

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Guest Editor

Department of Biology and Toxicology, Ashland University, Ashland, OH 44805, USA
Interests: bacteriophage; phage therapy; host range; phage evolution; phage receptor; phage-host co-evolution

Dr. Christine Schneider

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Guest Editor

Department of Biology, Carroll University, Waukesha, WI 53186 USA
Interests: bacteriophage; transduction; antibiotic resistance; phage therapeutics

Dr. Bryan Gibb

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Guest Editor

Department of Biological and Chemical Sciences, New York Institute of Technology, Old Westbury, NY 11568-8000, USA
Interests: bacteriophage; antibiotic resistance; phage therapy; wastewater ecology

Special Issue Information

Dear Colleagues,

Bacteriophages and other viruses can be considered highly evolved gene delivery vehicles that carry their genome payloads in metabolically inert virion particles between host cells. For many tailed bacteriophages, simply binding to the host cell receptor triggers a complex series of protein conformational changes that lead to the injection of the phage genome into the host cell. Other viruses rely on host cell endocytosis mechanisms that are activated upon binding of the viruses to cell receptors. While in most cases, these mechanisms lead to the viral genome entering the cell as part of the infection process, there are cases when the nucleic acids being delivered are not the viral genome. Probably the best known example of this is generalized transduction, in which a fragment of the host genome instead of the viral genome is packaged into a phage particle and the particle carries that fragment to another host cell where the DNA can be retained via recombination.

Many clever researchers have developed techniques to replace the virus genome in the virion particle with a virus genome that has non-virus genes or an entirely non-virus segment of nucleic acid. The applications of these genetically modified viruses can be quite varied including:

Targeted delivery of toxin genes to kill cells
Targeted delivery of genes encoding desirable traits to modify cellular function
Gene therapy
Phage vaccines

A related but very different use of virus particles is the attachment of toxins or other therapeutic molecules to the outside of the virus capsid, again using the receptor binding protein affinity for the cell receptor to direct the payload to the correct cells.

For this Special Issue, we invite authors to submit articles providing examples of the various uses of bacteriophages and other viruses to deliver some non-virus gene or molecule. Reviews, proposals and research reports are all welcome.

Prof. Paul Hyman
Dr. Christine Schneider
Dr. Bryan Gibb
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Bacteriophage
Transduction
Phage therapy
Gene therapy
Vaccine
Phage-mediated biocontrol
Gene transfer agent
Therapeutic genes
Genome modification

Published Papers (11 papers)

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Research

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19 pages, 5042 KiB

Open AccessArticle

Engineered Bacteriophage as a Delivery Vehicle for Antibacterial Protein, SASP

by James Cass, Anne Barnard and Heather Fairhead

Pharmaceuticals 2021, 14(10), 1038; https://doi.org/10.3390/ph14101038 - 12 Oct 2021

Cited by 12 | Viewed by 2807

Abstract

The difficulties in developing novel classes of antibacterials is leading to a resurgence of interest in bacteriophages as therapeutic agents, and in particular engineered phages that can be optimally designed. Here, pre-clinical microbiology assessment is presented of a Staphylococcus aureus phage engineered to deliver a gene encoding an antibacterial small acid soluble spore protein (SASP) and further, rendered non-lytic to give product SASPject PT1.2. PT1.2 has been developed initially for nasal decolonisation of S. aureus, including methicillin-resistant S. aureus. Time-kill curve assays were conducted with PT1.2 against a range of staphylococcal species, and serial passaging experiments were conducted to investigate the potential for resistance to develop. SASPject PT1.2 demonstrates activity against 100% of 225 geographically diverse S. aureus isolates, exquisite specificity for S. aureus, and a rapid speed of kill. The kinetics of S. aureus/PT1.2 interaction is examined together with demonstrating that PT1.2 activity is unaffected by the presence of human serum albumin. SASPject PT1.2 shows a low propensity for resistance to develop with no consistent shift in sensitivity in S. aureus cells passaged for up to 42 days. SASPject PT1.2 shows promise as a novel first-in-class antibacterial agent and demonstrates potential for the SASPject platform. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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14 pages, 2459 KiB

Open AccessArticle

In Vitro and In Vivo Gastrointestinal Survival of Non-Encapsulated and Microencapsulated Salmonella Bacteriophages: Implications for Bacteriophage Therapy in Poultry

by Laura Lorenzo-Rebenaque, Danish J. Malik, Pablo Catalá-Gregori, Clara Marin and Sandra Sevilla-Navarro

Pharmaceuticals 2021, 14(5), 434; https://doi.org/10.3390/ph14050434 - 06 May 2021

Cited by 14 | Viewed by 3141

Abstract

The therapeutic use of bacteriophages is recognized as a viable method to control Salmonella. Microencapsulation of phages in oral dosage forms may protect phages from inherent challenges of the gastrointestinal tract in chickens. Therefore, the main objective of this study was to assess the survival of Salmonella BP FGS011 (non-encapsulated and microencapsulated) through the gastrointestinal tract under in vitro as well as in vivo conditions after oral administration to 1-day-old chicks. To this end, the phage FGS011 was encapsulated in two different pH-responsive formulations with polymers Eudragit^® L100, and Eudragit^® S100 using the process of spray drying. Phages encapsulated in either of the two formulations were able to survive exposure to the proventriculus-gizzard in vitro conditions whereas free phages did not. Moreover, phages formulated in polymer Eudragit^® S100 would be better suited to deliver phage to the caeca in chickens. In the in vivo assay, no statistically significant differences were observed in the phage concentrations across the gastrointestinal tract for either the free phage or the encapsulated phage given to chicks. This suggested that the pH of the proventriculus/gizzard in young chicks is not sufficiently acidic to cause differential phage titre reductions, thereby allowing free phage survival in vivo. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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13 pages, 9428 KiB

Open AccessArticle

Luminescent Phage-Based Detection of Klebsiella pneumoniae: From Engineering to Diagnostics

by Lior Zelcbuch, Elad Yitzhaki, Olga Nissan, Eliya Gidron, Nufar Buchshtab, Edith Kario, Sharon Kredo-Russo, Naomi B. Zak and Merav Bassan

Pharmaceuticals 2021, 14(4), 347; https://doi.org/10.3390/ph14040347 - 09 Apr 2021

Cited by 6 | Viewed by 3409

Abstract

Bacteriophages (“phages”) infect and multiply within specific bacterial strains, causing lysis of their target. Due to the specific nature of these interactions, phages allow a high-precision approach for therapy which can also be exploited for the detection of phage-sensitive pathogens associated with chronic diseases due to gut microbiome imbalance. As rapid phage-mediated detection assays becoming standard-of-care diagnostic tools, they will advance the more widespread application of phage therapy in a precision approach. Using a conventional method and a new cloning approach to develop luminescent phages, we engineered two phages that specifically detect a disease-associated microbial strain. We performed phage sensitivity assays in liquid culture and in fecal matrices and tested the stability of spiked fecal samples stored under different conditions. Different reporter gene structures and genome insertion sites were required to successfully develop the two nluc-reporter phages. The reporter phages detected spiked bacteria in five fecal samples with high specificity. Fecal samples stored under different conditions for up to 30 days did not display major losses in reporter-phage-based detection. Luminescent phage-based diagnostics can provide a rapid co-diagnostic tool to guide the growing field of phage therapy, particularly for a precision-based approach to chronic diseases treatment. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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21 pages, 1556 KiB

Open AccessArticle

ε²-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages

by David Sáez Moreno, Zehra Visram, Michele Mutti, Marcela Restrepo-Córdoba, Susana Hartmann, Ana Isabel Kremers, Lenka Tišáková, Susanne Schertler, Johannes Wittmann, Benham Kalali, Stefan Monecke, Ralf Ehricht, Grégory Resch and Lorenzo Corsini

Pharmaceuticals 2021, 14(4), 325; https://doi.org/10.3390/ph14040325 - 02 Apr 2021

Cited by 19 | Viewed by 9655

Abstract

Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) composed to reflect the prevalence of S. aureus clonal complexes in human infections. The plaquing host ranges (PHR) of the wild type phages were in the range of 51% to 60%. We also measured what we called the kinetic host range (KHR), i.e., the percentage of strains for which growth in suspension was suppressed for 24 h. The KHR of the wild type phages ranged from 2% to 49%, substantially lower than the PHRs. To improve the KHR and other key pharmaceutical properties, we bred the phages by mixing and propagating cocktails on a subset of S. aureus strains. These bred phages, which we termed evolution-squared (ε²) phages, have broader KHRs up to 64% and increased virulence compared to the ancestors. The ε²-phages with the broadest KHR have genomes intercrossed from up to three different ancestors. We composed a cocktail of three ε²-phages with an overall KHR of 92% and PHR of 96% on 110 S. aureus strains and called it PM-399. PM-399 has a lower propensity to resistance formation than the standard of care antibiotics vancomycin, rifampicin, or their combination, and no resistance was observed in laboratory settings (detection limit: 1 cell in 10¹¹). In summary, ε²-phages and, in particular PM-399, are promising candidates for an alternative treatment of S. aureus infections. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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13 pages, 759 KiB

Open AccessArticle

Modification of Bacteriophages to Increase Their Association with Lung Epithelium Cells In Vitro

by Aurelija M. Grigonyte, Alexia Hapeshi, Chrystala Constantinidou and Andrew Millard

Pharmaceuticals 2021, 14(4), 308; https://doi.org/10.3390/ph14040308 - 01 Apr 2021

Cited by 5 | Viewed by 3188

Abstract

There is currently a renaissance in research on bacteriophages as alternatives to antibiotics. Phage specificity to their bacterial host, in addition to a plethora of other advantages, makes them ideal candidates for a broad range of applications, including bacterial detection, drug delivery, and phage therapy in particular. One issue obstructing phage efficiency in phage therapy settings is their poor localization to the site of infection in the human body. Here, we engineered phage T7 with lung tissue targeting homing peptides. We then used in vitro studies to demonstrate that the engineered T7 phages had a more significant association with the lung epithelium cells than wild-type T7. In addition, we showed that, in general, there was a trend of increased association of engineered phages with the lung epithelium cells but not mouse fibroblast cells, allowing for targeted tissue specificity. These results indicate that appending phages with homing peptides would potentially allow for greater phage concentrations and greater efficacy at the infection site. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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Review

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16 pages, 2068 KiB

Open AccessReview

Manufacturing Bacteriophages (Part 1 of 2): Cell Line Development, Upstream, and Downstream Considerations

by Tayfun Tanir, Marvin Orellana, Aster Escalante, Carolina Moraes de Souza and Michael S. Koeris

Pharmaceuticals 2021, 14(9), 934; https://doi.org/10.3390/ph14090934 - 17 Sep 2021

Cited by 4 | Viewed by 4421

Abstract

Within this first part of the two-part series on phage manufacturing, we will give an overview of the process leading to bacteriophages as a drug substance, before covering the formulation into a drug product in the second part. The principal goal is to provide the reader with a comprehensive framework of the challenges and opportunities that present themselves when developing manufacturing processes for bacteriophage-based products. We will examine cell line development for manufacture, upstream and downstream processes, while also covering the additional opportunities that engineered bacteriophages present. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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11 pages, 1987 KiB

Open AccessReview

Manufacturing Bacteriophages (Part 2 of 2): Formulation, Analytics and Quality Control Considerations

by Carolina Moraes de Souza, Tayfun Tanir, Marvin Orellana, Aster Escalante and Michael Sandor Koeris

Pharmaceuticals 2021, 14(9), 895; https://doi.org/10.3390/ph14090895 - 02 Sep 2021

Cited by 5 | Viewed by 4459

Abstract

Within this second piece of the two-part series of phage manufacturing considerations, we are examining the creation of a drug product from a drug substance in the form of formulation, through to fill-finish. Formulation of a drug product, in the case of bacteriophage products, is often considered only after many choices have been made in the development and manufacture of a drug substance, increasing the final product development timeline and difficulty of achieving necessary performance parameters. As with the preceding review in this sequence, we aim to provide the reader with a framework to be able to consider pharmaceutical development choices for the formulation of a bacteriophage-based drug product. The intent is to sensitize and highlight the tradeoffs that are necessary in the development of a finished drug product, and to be able to take the entire spectrum of tradeoffs into account, starting with early-stage R&D efforts. Furthermore, we are arming the reader with an overview of historical and current analytical methods with a special emphasis on most relevant and most widely available methods. Bacteriophages pose some challenges that are related to but also separate from eukaryotic viruses. Last, but not least, we close this two-part series by briefly discussing quality control (QC) aspects of a bacteriophage-based product, taking into consideration the opportunities and challenges that engineered bacteriophages uniquely present and offer. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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12 pages, 762 KiB

Open AccessReview

RNA Phage VLP-Based Vaccine Platforms

by David S. Peabody, Julianne Peabody, Steven B. Bradfute and Bryce Chackerian

Pharmaceuticals 2021, 14(8), 764; https://doi.org/10.3390/ph14080764 - 04 Aug 2021

Cited by 8 | Viewed by 3669

Abstract

Virus-like particles from a variety of RNA bacteriophages have turned out to be useful platforms for delivery of vaccine antigens in a highly immunogenic format. Here we update the current state of development of RNA phage VLPs as platforms for presentation of diverse [...] Read more.

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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19 pages, 1609 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Many Applications of Engineered Bacteriophages—An Overview

by Bryan Gibb, Paul Hyman and Christine L. Schneider

Pharmaceuticals 2021, 14(7), 634; https://doi.org/10.3390/ph14070634 - 30 Jun 2021

Cited by 36 | Viewed by 6460

Abstract

Since their independent discovery by Frederick Twort in 1915 and Felix d’Herelle in 1917, bacteriophages have captured the attention of scientists for more than a century. They are the most abundant organisms on the planet, often outnumbering their bacterial hosts by tenfold in a given environment, and they constitute a vast reservoir of unexplored genetic information. The increased prevalence of antibiotic resistant pathogens has renewed interest in the use of naturally obtained phages to combat bacterial infections, aka phage therapy. The development of tools to modify phages, genetically or chemically, combined with their structural flexibility, cargo capacity, ease of propagation, and overall safety in humans has opened the door to a myriad of applications. This review article will introduce readers to many of the varied and ingenious ways in which researchers are modifying phages to move them well beyond their innate ability to target and kill bacteria. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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19 pages, 358 KiB

Open AccessReview

Formulations for Bacteriophage Therapy and the Potential Uses of Immobilization

by Daniel Rosner and Jason Clark

Pharmaceuticals 2021, 14(4), 359; https://doi.org/10.3390/ph14040359 - 13 Apr 2021

Cited by 39 | Viewed by 5350

Abstract

The emergence of antibiotic-resistant pathogens is becoming increasingly problematic in the treatment of bacterial diseases. This has led to bacteriophages receiving increased attention as an alternative form of treatment. Phages are effective at targeting and killing bacterial strains of interest and have yielded encouraging results when administered as part of a tailored treatment to severely ill patients as a last resort. Despite this, success in clinical trials has not always been as forthcoming, with several high-profile trials failing to demonstrate the efficacy of phage preparations in curing diseases of interest. Whilst this may be in part due to reasons surrounding poor phage selection and a lack of understanding of the underlying disease, there is growing consensus that future success in clinical trials will depend on effective delivery of phage therapeutics to the area of infection. This can be achieved using bacteriophage formulations instead of purely liquid preparations. Several encapsulation-based strategies can be applied to produce phage formulations and encouraging results have been observed with respect to efficacy as well as long term phage stability. Immobilization-based approaches have generally been neglected for the production of phage therapeutics but could also offer a viable alternative. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

16 pages, 1833 KiB

Open AccessReview

Bacteriophages as Therapeutic and Diagnostic Vehicles in Cancer

by Valentina Foglizzo and Serena Marchiò

Pharmaceuticals 2021, 14(2), 161; https://doi.org/10.3390/ph14020161 - 17 Feb 2021

Cited by 29 | Viewed by 6458

Abstract

Evolution of nanomedicine is the re-design of synthetic and biological carriers to implement novel theranostic platforms. In recent years, bacteriophage research favors this process, which has opened up new roads in drug and gene delivery studies. By displaying antibodies, peptides, or proteins on the surface of different bacteriophages through the phage display technique, it is now possible to unravel specific molecular determinants of both cancer cells and tumor-associated microenvironmental molecules. Downstream applications are manifold, with peptides being employed most of the times to functionalize drug carriers and improve their therapeutic index. Bacteriophages themselves were proven, in this scenario, to be good carriers for imaging molecules and therapeutics as well. Moreover, manipulation of their genetic material to stably vehiculate suicide genes within cancer cells substantially changed perspectives in gene therapy. In this review, we provide examples of how amenable phages can be used as anticancer agents, especially because their systemic administration is possible. We also provide some insights into how their immunogenic profile can be modulated and exploited in immuno-oncology for vaccine production. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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