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Phage Therapy and Phage-Mediated Biological Control

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 84705

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Special Issue Editors

Prof. Dr. Stephen T. Abedon

E-Mail Website
Guest Editor

Department of Microbiology, The Ohio State University, Columbus, OH 44906, USA
Interests: phage ecology; phage evolutionary ecology; phage therapy; phage therapy pharmacology; phage history
Special Issues, Collections and Topics in MDPI journals

Dr. Diana R. Alves

E-Mail Website
Co-Guest Editor

Department of Pharmacology and Biomolecular Sciences, Moulsecomb, University of Brighton, Brighton BN7 4GJ, UK
Interests: bacteriophage therapy; bacteriophage biology; infectious diseases; biofilms

Special Issue Information

Dear Colleagues,

Bacteriophages or phages – the viruses of bacteria – are the most abundant and potentially most diverse organisms on Earth. The majority of these viruses are lytic, meaning that, upon producing new phages, they not only kill but also lyse their bacterial hosts. Most phages target these hosts with high precision, resulting in easily predicted pharmacodynamics. Phages, in other words, have been evolving for roughly three billion years to be extremely effective at killing bacteria but, properly chosen, have little potential to do much else, such as displaying toxicity towards bodies or environments.

Given these properties, phages have at least a potential to serve as antibacterial agents both within and outside of medicine. They have in fact been used as antibacterials clinically for nearly 100 years, longer even than chemical antibiotics have been known to science. Indeed, they represent highly diverse, easily discovered, readily characterized, inexpensively produced, low-toxicity antibacterial agents. Were we to include bacteriophages among ‘antibiotics’ then there arguably would be no antibiotic crisis.

In this Special Issue we seek submissions broadly pertaining to the subject of phage therapy, the clinical or veterinary use of bacterial viruses as antibacterial “drugs”, or, more generally, the use of phages as antibacterial biological control agents.

Related publications:

1. Phage therapy pharmacology
https://www.ncbi.nlm.nih.gov/pubmed/20214606
2. Ecology of Anti-Biofilm Agents I: Antibiotics versus Bacteriophages
https://www.ncbi.nlm.nih.gov/pubmed/26371010
3. Ecology of Anti-Biofilm Agents II: Bacteriophage Exploitation and Biocontrol of Biofilm Bacteria
https://www.ncbi.nlm.nih.gov/pubmed/26371011

Prof. Stephen T. Abedon
Dr. Diana R. Alves
Guest Editors

Submission

Manuscripts should be pre-submitted directly Stephen Abedon ([email protected]) for initial editing. Research articles should strive to conform to the guidelines outlined in [editorial: “Phage Therapy Pharmacology: What Information Phage Therapy Studies Should Report”]. Following this initial editing, manuscripts should be submitted for peer review as follows:

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a 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 quarterly 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 850 CHF (Swiss Francs).

Keywords

phage therapy
clinical practice
veterinary use
experimental phage therapy
animal study
regulation
alternative licensing
pharmacology
pharmacodynamics
pharmacokinetics
phage-mediated biocontrol of bacteria
biocontrol
food safety
plant disease biocontrol
phage isolation
phage characterization

Published Papers (10 papers)

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Research

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22 pages, 2697 KiB

Open AccessArticle

Efficacy of Bacteriophages Against Staphylococcus aureus Isolates from Bovine Mastitis

by Isabel Titze, Tatiana Lehnherr, Hansjörg Lehnherr and Volker Krömker

Pharmaceuticals 2020, 13(3), 35; https://doi.org/10.3390/ph13030035 - 26 Feb 2020

Cited by 23 | Viewed by 5040

Abstract

The lytic efficacy of bacteriophages against Staphylococcus aureus isolates from bovine milk was investigated in vitro, regarding possible applications in the therapy of udder inflammation caused by bacterial infections (mastitis). The host range of sequenced, lytic bacteriophages was determined against a collection of 92 Staphylococcus (S.) aureus isolates. The isolates originated from quarter foremilk samples of clinical and subclinical mastitis cases. A spot test and a subsequent plaque assay were used to determine the phage host range. According to their host range, propagation and storage properties, three phages, STA1.ST29, EB1.ST11, and EB1.ST27, were selected for preparing a bacteriophage mixture (1:1:1), which was examined for its lytic activity against S. aureus in pasteurized and raw milk. It was found that almost two thirds of the isolates could be lysed by at least one of the tested phages. The bacteriophage mixture was able to reduce the S. aureus germ density in pasteurized milk and its reduction ability was maintained in raw milk, with only a moderate decrease compared to the results in pasteurized milk. The significant reduction ability of the phage mixture in raw milk promotes further in vivo investigation. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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14 pages, 1344 KiB

Open AccessArticle

Microencapsulation of Salmonella-Specific Bacteriophage Felix O1 Using Spray-Drying in a pH-Responsive Formulation and Direct Compression Tableting of Powders into a Solid Oral Dosage Form

by Gurinder K. Vinner, Zahra Rezaie-Yazdi, Miika Leppanen, Andrew G.F. Stapley, Mark C. Leaper and Danish J. Malik

Pharmaceuticals 2019, 12(1), 43; https://doi.org/10.3390/ph12010043 - 22 Mar 2019

Cited by 42 | Viewed by 7633

Abstract

The treatment of enteric bacterial infections using oral bacteriophage therapy can be challenging since the harsh acidic stomach environment renders phages inactive during transit through the gastrointestinal tract. Solid oral dosage forms allowing site-specific gastrointestinal delivery of high doses of phages, e.g., using a pH or enzymatic trigger, would be a game changer for the nascent industry trying to demonstrate the efficacy of phages, including engineered phages for gut microbiome modulation in expensive clinical trials. Spray-drying is a scalable, low-cost process for producing pharmaceutical agents in dry powder form. Encapsulation of a model Salmonella-specific phage (Myoviridae phage Felix O1) was carried out using the process of spray-drying, employing a commercially available Eudragit S100^® pH-responsive anionic copolymer composed of methyl methacrylate-co-methacrylic acid formulated with trehalose. Formulation and processing conditions were optimised to improve the survival of phages during spray-drying, and their subsequent protection upon exposure to simulated gastric acidity was demonstrated. Addition of trehalose to the formulation was shown to protect phages from elevated temperatures and desiccation encountered during spray-drying. Direct compression of spray-dried encapsulated phages into tablets was shown to significantly improve phage protection upon exposure to simulated gastric fluid. The results reported here demonstrate the significant potential of spray-dried pH-responsive formulations for oral delivery of bacteriophages targeting gastrointestinal applications. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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14 pages, 1607 KiB

Open AccessArticle

Parallel Evolution of Host-Attachment Proteins in Phage PP01 Populations Adapting to Escherichia coli O157:H7

by Chidiebere Akusobi, Benjamin K. Chan, Elizabeth S.C.P. Williams, John E. Wertz and Paul E. Turner

Pharmaceuticals 2018, 11(2), 60; https://doi.org/10.3390/ph11020060 - 20 Jun 2018

Cited by 18 | Viewed by 5080

Abstract

The emergence of antibiotic resistance has sparked interest in phage therapy, which uses virulent phages as antibacterial agents. Bacteriophage PP01 has been studied for potential bio-control of Escherichia coli O157:H7, its natural host, but in the laboratory, PP01 can be inefficient at killing this bacterium. Thus, the goal of this study was to improve the therapeutic potential of PP01 through short-term experimental evolution. Four replicate populations of PP01 were serially passaged 21 times on non-evolving E. coli O157:H7 with the prediction that the evolved phage populations would adsorb faster and more efficiently kill the host bacteria. Dead-cell adsorption assays and in vitro killing assays confirmed that evolved viruses improved their adsorption ability on E. coli O157:H7, and adapted to kill host bacteria faster than the wildtype ancestor. Sequencing of candidate tail-fiber genes revealed that the phage populations evolved in parallel; the lineages shared two point mutations in gp38 that encodes a host recognition protein, and surprisingly shared a ~600 bp deletion in gp37 that encodes the distal tail fibers. In contrast, no mutations were observed in the gp12 gene encoding PP01’s short tail fibers. We discuss the functional role of the observed mutations, including the possible adaptive role of the evolved deletions. This study demonstrates how experimental evolution can be used to select for viral traits that improve phage attack of an important bacterial pathogen, and that the molecular targets of selection include loci contributing to cell attachment and phage virulence. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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22 pages, 19514 KiB

Open AccessFeature PaperArticle

Novel N4-Like Bacteriophages of Pectobacterium atrosepticum

by Colin Buttimer, Hanne Hendrix, Alan Lucid, Horst Neve, Jean-Paul Noben, Charles Franz, Jim O’Mahony, Rob Lavigne and Aidan Coffey

Pharmaceuticals 2018, 11(2), 45; https://doi.org/10.3390/ph11020045 - 14 May 2018

Cited by 39 | Viewed by 6811

Abstract

Pectobacterium atrosepticum is an economically important phytopathogen that is responsible for potato blackleg and soft rot, and for which current control strategies are limited. In this study, stem samples of potato crops exhibiting blackleg were taken from three farms in Co. Cork, Ireland, and they were found to be infected with P. atrosepticum. Three closely related bacteriophages (phages) that are specific to this phytopathogen were isolated and characterized, namely vB_PatP_CB1, vB_PatP_CB3, and vB_PatP_CB4 (abbreviated as CB1, CB3, and CB4). Both CB1 and CB3 were determined to infect 12 strains and CB4 10 strains of the 19 strains of P. atrosepticum tested. Morphology, latent periods, burst sizes, and their stability at various temperatures and pHs were also examined. Genome sequencing of the three phages revealed that they shared a minimum nucleotide identity of 93% with each other. Their genomes exhibited an Enquartavirinae genome organization, possessing several conserved proteins that were associated with phages of this group, like the type species Escherichia virus N4. Tandem electrospray ionization-mass spectrometry (ESI-MS/MS) allowed for the identification of ten structural proteins that form the virion of CB1, six that are conserved in phage N4. Biocontrol experiments demonstrated that the phages suppress soft rot formation upon co-inoculation with P. atrosepticum on whole tubers. The results of this study indicate that CB1 related phages could be good candidates for phage-based control. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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14 pages, 3690 KiB

Open AccessCommunication

Computational Modelling of Large Scale Phage Production Using a Two-Stage Batch Process

by Konrad Krysiak-Baltyn, Gregory J. O. Martin and Sally L. Gras

Pharmaceuticals 2018, 11(2), 31; https://doi.org/10.3390/ph11020031 - 08 Apr 2018

Cited by 22 | Viewed by 5809

Abstract

Cost effective and scalable methods for phage production are required to meet an increasing demand for phage, as an alternative to antibiotics. Computational models can assist the optimization of such production processes. A model is developed here that can simulate the dynamics of phage population growth and production in a two-stage, self-cycling process. The model incorporates variable infection parameters as a function of bacterial growth rate and employs ordinary differential equations, allowing application to a setup with multiple reactors. The model provides simple cost estimates as a function of key operational parameters including substrate concentration, feed volume and cycling times. For the phage and bacteria pairing examined, costs and productivity varied by three orders of magnitude, with the lowest cost found to be most sensitive to the influent substrate concentration and low level setting in the first vessel. An example case study of phage production is also presented, showing how parameter values affect the production costs and estimating production times. The approach presented is flexible and can be used to optimize phage production at laboratory or factory scale by minimizing costs or maximizing productivity. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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19 pages, 4517 KiB

Open AccessFeature PaperArticle

Characterization of the Lytic Capability of a LysK-Like Endolysin, Lys-phiSA012, Derived from a Polyvalent Staphylococcus aureus Bacteriophage

by Jumpei Fujiki, Tomohiro Nakamura, Takaaki Furusawa, Hazuki Ohno, Hiromichi Takahashi, Junya Kitana, Masaru Usui, Hidetoshi Higuchi, Yasunori Tanji, Yutaka Tamura and Hidetomo Iwano

Pharmaceuticals 2018, 11(1), 25; https://doi.org/10.3390/ph11010025 - 24 Feb 2018

Cited by 29 | Viewed by 7944

Abstract

Antibiotic-resistant bacteria (ARB) have spread widely and rapidly, with their increased occurrence corresponding with the increased use of antibiotics. Infections caused by Staphylococcus aureus have a considerable negative impact on human and livestock health. Bacteriophages and their peptidoglycan hydrolytic enzymes (endolysins) have received significant attention as novel approaches against ARB, including S. aureus. In the present study, we purified an endolysin, Lys-phiSA012, which harbors a cysteine/histidine-dependent amidohydrolase/peptidase (CHAP) domain, an amidase domain, and a SH3b cell wall binding domain, derived from a polyvalent S. aureus bacteriophage which we reported previously. We demonstrate that Lys-phiSA012 exhibits high lytic activity towards staphylococcal strains, including methicillin-resistant S. aureus (MRSA). Analysis of deletion mutants showed that only mutants possessing the CHAP and SH3b domains could lyse S. aureus, indicating that lytic activity of the CHAP domain depended on the SH3b domain. The presence of at least 1 mM Ca²⁺ and 100 µM Zn²⁺ enhanced the lytic activity of Lys-phiSA012 in a turbidity reduction assay. Furthermore, a minimum inhibitory concentration (MIC) assay showed that the addition of Lys-phiSA012 decreased the MIC of oxacillin. Our results suggest that endolysins are a promising approach for replacing current antimicrobial agents and may contribute to the proper use of antibiotics, leading to the reduction of ARB. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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Review

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23 pages, 1090 KiB

Open AccessReview

Phages for Phage Therapy: Isolation, Characterization, and Host Range Breadth

by Paul Hyman

Pharmaceuticals 2019, 12(1), 35; https://doi.org/10.3390/ph12010035 - 11 Mar 2019

Cited by 265 | Viewed by 22886

Abstract

For a bacteriophage to be useful for phage therapy it must be both isolated from the environment and shown to have certain characteristics beyond just killing strains of the target bacterial pathogen. These include desirable characteristics such as a relatively broad host range and a lack of other characteristics such as carrying toxin genes and the ability to form a lysogen. While phages are commonly isolated first and subsequently characterized, it is possible to alter isolation procedures to bias the isolation toward phages with desirable characteristics. Some of these variations are regularly used by some groups while others have only been shown in a few publications. In this review I will describe (1) isolation procedures and variations that are designed to isolate phages with broader host ranges, (2) characterization procedures used to show that a phage may have utility in phage therapy, including some of the limits of such characterization, and (3) results of a survey and discussion with phage researchers in industry and academia on the practice of characterization of phages. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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25 pages, 459 KiB

Open AccessReview

Enhancing Whole Phage Therapy and Their Derived Antimicrobial Enzymes through Complex Formulation

by Callum J. Cooper, Shazeeda Koonjan and Anders S. Nilsson

Pharmaceuticals 2018, 11(2), 34; https://doi.org/10.3390/ph11020034 - 19 Apr 2018

Cited by 29 | Viewed by 6310

Abstract

The resurgence of research into phage biology and therapy is, in part, due to the increasing need for novel agents to treat multidrug-resistant infections. Despite a long clinical history in Eastern Europe and initial success within the food industry, commercialized phage products have yet to enter other sectors. This relative lack of success is, in part, due to the inherent biological limitations of whole phages. These include (but are not limited to) reaching target sites at sufficiently high concentrations to establish an infection which produces enough progeny phages to reduce the bacterial population in a clinically meaningful manner and the limited host range of some phages. Conversely, parallels can be drawn between antimicrobial enzymes derived from phages and conventional antibiotics. In the current article the biological limitations of whole phage-based therapeutics and their derived antimicrobial enzymes will be discussed. In addition, the ability of more complex formulations to address these issues, in the context of medical and non-medical applications, will also be included. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

12 pages, 1690 KiB

Open AccessReview

Semi-Solid and Solid Dosage Forms for the Delivery of Phage Therapy to Epithelia

by Teagan L. Brown, Steve Petrovski, Hiu Tat Chan, Michael J. Angove and Joseph Tucci

Pharmaceuticals 2018, 11(1), 26; https://doi.org/10.3390/ph11010026 - 26 Feb 2018

Cited by 23 | Viewed by 8092

Abstract

The delivery of phages to epithelial surfaces for therapeutic outcomes is a realistic proposal, and indeed one which is being currently tested in clinical trials. This paper reviews some of the known research on formulation of phages into semi-solid dosage forms such as creams, ointments and pastes, as well as solid dosage forms such as troches (or lozenges and pastilles) and suppositories/pessaries, for delivery to the epithelia. The efficacy and stability of these phage formulations is discussed, with a focus on selection of optimal semi-solid bases for phage delivery. Issues such as the need for standardisation of techniques for formulation as well as for assessment of efficacy are highlighted. These are important when trying to compare results from a range of experiments and across different delivery bases. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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Other

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215 KiB

Open AccessOpinion

Information Phage Therapy Research Should Report

by Stephen T. Abedon

Pharmaceuticals 2017, 10(2), 43; https://doi.org/10.3390/ph10020043 - 30 Apr 2017

Cited by 56 | Viewed by 7474

Abstract

Bacteriophages, or phages, are viruses which infect bacteria. A large subset of phages infect bactericidally and, consequently, for nearly one hundred years have been employed as antibacterial agents both within and outside of medicine. Clinically these applications are described as phage or bacteriophage therapy. Alternatively, and especially in the treatment of environments, this practice instead may be described as a phage-mediated biocontrol of bacteria. Though the history of phage therapy has involved substantial clinical experimentation, current standards along with drug regulations have placed a premium on preclinical approaches, i.e., animal experiments. As such, it is important for preclinical experiments not only to be held to high standards but also to be reported in a manner which improves translation to clinical utility. Here I address this latter issue, that of optimization of reporting of preclinical as well as clinical experiments. I do this by providing a list of pertinent information and data which, in my opinion, phage therapy experiments ought to present in publications, along with tips for best practices. The goal is to improve the ability of readers to gain relevant information from reports on phage therapy research, to allow other researchers greater potential to repeat or extend findings, to ease transitions from preclinical to clinical development, and otherwise simply to improve phage therapy experiments. Targeted are not just authors but also reviewers, other critical readers, writers of commentaries, and, perhaps, formulators of guidelines or policy. Though emphasizing therapy, many points are applicable to phage-mediated biocontrol of bacteria more generally. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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