Special Issue "Bacteriophages as Therapeutic Delivery Vehicles"

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

Deadline for manuscript submissions: 30 July 2021.

Special Issue Editors

Prof. Paul Hyman
E-Mail Website
Guest Editor
Department of Biology and Toxicology, Ashland Univeristy, Ashland, OH, 44805 USA
Interests: bacteriphage; host range; phage therapy; phage ecology
Dr. Christine Schneider
E-Mail Website
Guest Editor
Department of Biology, Carroll University, Waukesha, WI, 53186 USA
Interests: bacteriophage; transduction; antibiotic resistance; phage therapeutics
Dr. Bryan Gibb
E-Mail Website
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

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 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 (6 papers)

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Research

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Article
In Vitro and In Vivo Gastrointestinal Survival of Non-Encapsulated and Microencapsulated Salmonella Bacteriophages: Implications for Bacteriophage Therapy in Poultry
Pharmaceuticals 2021, 14(5), 434; https://doi.org/10.3390/ph14050434 - 06 May 2021
Viewed by 510
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 [...] Read more.
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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Article
Luminescent Phage-Based Detection of Klebsiella pneumoniae: From Engineering to Diagnostics
Pharmaceuticals 2021, 14(4), 347; https://doi.org/10.3390/ph14040347 - 09 Apr 2021
Viewed by 431
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 [...] Read more.
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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Article
ε2-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages
Pharmaceuticals 2021, 14(4), 325; https://doi.org/10.3390/ph14040325 - 02 Apr 2021
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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) [...] Read more.
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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Article
Modification of Bacteriophages to Increase Their Association with Lung Epithelium Cells In Vitro
Pharmaceuticals 2021, 14(4), 308; https://doi.org/10.3390/ph14040308 - 01 Apr 2021
Viewed by 740
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 [...] Read more.
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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Review
Formulations for Bacteriophage Therapy and the Potential Uses of Immobilization
Pharmaceuticals 2021, 14(4), 359; https://doi.org/10.3390/ph14040359 - 13 Apr 2021
Cited by 1 | Viewed by 834
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 [...] Read more.
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)
Review
Bacteriophages as Therapeutic and Diagnostic Vehicles in Cancer
Pharmaceuticals 2021, 14(2), 161; https://doi.org/10.3390/ph14020161 - 17 Feb 2021
Viewed by 873
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 [...] Read more.
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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