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Special Issue "Hurdles for Phage Therapy (PT) to Become a Reality"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Bacterial Viruses".

Deadline for manuscript submissions: 15 February 2019

Special Issue Editor

Guest Editor
Dr. Harald Brüssow

Nestlé Research Center, Lausanne, Switzerland
E-Mail
Interests: Diarrhea, Bacteriophages, Microbiota, Nutrition and Health, Pediatrics

Special Issue Information

Dear Colleagues,

With the rise of antibiotic resistance to critical levels in a number of important bacterial pathogens, a return to a pre-antibiotic era is feared. Consequently, interest into alternative antimicrobial agents has grown. Phage therapy is a potential alternative or an adjunct to antibiotics. Indeed, commercial phage cocktails against numerous bacterial infections are available as over-the-counter drugs in several member states of the former Soviet Union. However, only few exploratory controlled human phage therapy trials have been conducted outside the Soviet Union and no phage products have so far been registered for medical use in Western countries.

In this Special Issue of Viruses, we want to explore reasons for the lack of clinical progress in the field of phage therapy by conducting a gap analysis. Particularly welcome are critical analyses of our knowledge gaps on phage-pathogen interaction in animal or human hosts, articles that suggest regulatory requirements for such medical phage products, contributions that discuss models to finance phage production and controlled clinical trials, and discussions on the role of governmental and international health agencies in this process. Phage therapy will not be a panacea and we invite manuscripts that identify infectious diseases that are likely to respond to phage therapy.

Specific knowledge gaps:

1)   What in vitro phenotypes of phages could guide the selection of phages with suitable in vivo phenotype for PT?
2)   Is metagenome analysis from natural infection sites in humans a better way to identify phages with suitable in vivo replication potential?
3)   The problem of producing the therapeutically phage on pathogenic vs. non-pathogenic production strains.
4)   Purification, formulation and genetic safety assessment of the produced phages.
5)   Resistance development to phages occurring during PT.
6)   The unchartered area of phage-bacterium interaction within the mammalian or avian host.

Practical aspects:

7)   Is it possible to formulate a set of rules with respect to infection type, which predict successful interventions?
8)   Learning lessons from previous clinical trials.
9)   The regulatory framework for PT.
10) Need PT trials be organized by governmental agencies?
11) NGO and crowd funding for PT in developing countries.

Dr. Harald Brüssow
Guest Editor

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. Viruses 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 1600 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

  • Phage therapy
  • phage phenotypes
  • infection targets
  • in vivo phage-bacterium interaction
  • clinical trial organization

Published Papers (19 papers)

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Research

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Open AccessArticle Antibiotic Therapy Using Phage Depolymerases: Robustness Across a Range of Conditions
Viruses 2018, 10(11), 622; https://doi.org/10.3390/v10110622
Received: 26 October 2018 / Revised: 9 November 2018 / Accepted: 10 November 2018 / Published: 12 November 2018
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Abstract
Phage-derived depolymerases directed against bacterial capsules are showing therapeutic promise in various animal models of infection. However, individual animal model studies are often constrained by use of highly specific protocols, such that results may not generalize to even slight modifications. Here we explore
[...] Read more.
Phage-derived depolymerases directed against bacterial capsules are showing therapeutic promise in various animal models of infection. However, individual animal model studies are often constrained by use of highly specific protocols, such that results may not generalize to even slight modifications. Here we explore the robustness of depolymerase therapies shown to succeed in a previous study of mice. Treatment success rates were reduced by treatment delay, more so for some enzymes than others: K1- and K5 capsule-degrading enzymes retained partial efficacy on delay, while K30 depolymerase did not. Phage were superior to enzymes under delayed treatment only for K1. Route of administration (intramuscular versus intraperitoneal) mattered for success of K1E, possibly for K1F, not for K1H depolymerase. Significantly, K1 capsule-degrading enzymes proved highly successful when using immune-suppressed, leukopenic mice, even with delayed treatment. Evolution of bacteria resistant to K1-degrading enzymes did not thwart therapeutic success in leukopenic mice, likely because resistant bacteria were avirulent. In combination with previous studies these results continue to support the efficacy of depolymerases as antibacterial agents in vivo, but system-specific details are becoming evident. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessArticle Characterizing Phage Genomes for Therapeutic Applications
Viruses 2018, 10(4), 188; https://doi.org/10.3390/v10040188
Received: 13 March 2018 / Revised: 6 April 2018 / Accepted: 9 April 2018 / Published: 10 April 2018
Cited by 1 | PDF Full-text (10429 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Multi-drug resistance is increasing at alarming rates. The efficacy of phage therapy, treating bacterial infections with bacteriophages alone or in combination with traditional antibiotics, has been demonstrated in emergency cases in the United States and in other countries, however remains to be approved
[...] Read more.
Multi-drug resistance is increasing at alarming rates. The efficacy of phage therapy, treating bacterial infections with bacteriophages alone or in combination with traditional antibiotics, has been demonstrated in emergency cases in the United States and in other countries, however remains to be approved for wide-spread use in the US. One limiting factor is a lack of guidelines for assessing the genomic safety of phage candidates. We present the phage characterization workflow used by our team to generate data for submitting phages to the Federal Drug Administration (FDA) for authorized use. Essential analysis checkpoints and warnings are detailed for obtaining high-quality genomes, excluding undesirable candidates, rigorously assessing a phage genome for safety and evaluating sequencing contamination. This workflow has been developed in accordance with community standards for high-throughput sequencing of viral genomes as well as principles for ideal phages used for therapy. The feasibility and utility of the pipeline is demonstrated on two new phage genomes that meet all safety criteria. We propose these guidelines as a minimum standard for phages being submitted to the FDA for review as investigational new drug candidates. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessArticle Rapid Identification of Intact Staphylococcal Bacteriophages Using Matrix-Assisted Laser Desorption Ionization-Time-of-Flight Mass Spectrometry
Viruses 2018, 10(4), 176; https://doi.org/10.3390/v10040176
Received: 13 March 2018 / Revised: 1 April 2018 / Accepted: 2 April 2018 / Published: 4 April 2018
Cited by 1 | PDF Full-text (1152 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Staphylococcus aureus is a major causative agent of infections associated with hospital environments, where antibiotic-resistant strains have emerged as a significant threat. Phage therapy could offer a safe and effective alternative to antibiotics. Phage preparations should comply with quality and safety requirements; therefore,
[...] Read more.
Staphylococcus aureus is a major causative agent of infections associated with hospital environments, where antibiotic-resistant strains have emerged as a significant threat. Phage therapy could offer a safe and effective alternative to antibiotics. Phage preparations should comply with quality and safety requirements; therefore, it is important to develop efficient production control technologies. This study was conducted to develop and evaluate a rapid and reliable method for identifying staphylococcal bacteriophages, based on detecting their specific proteins using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling that is among the suggested methods for meeting the regulations of pharmaceutical authorities. Five different phage purification techniques were tested in combination with two MALDI-TOF MS matrices. Phages, either purified by CsCl density gradient centrifugation or as resuspended phage pellets, yielded mass spectra with the highest information value if ferulic acid was used as the MALDI matrix. Phage tail and capsid proteins yielded the strongest signals whereas the culture conditions had no effect on mass spectral quality. Thirty-seven phages from Myoviridae, Siphoviridae or Podoviridae families were analysed, including 23 siphophages belonging to the International Typing Set for human strains of S. aureus, as well as phages in preparations produced by Microgen, Bohemia Pharmaceuticals and MB Pharma. The data obtained demonstrate that MALDI-TOF MS can be used to effectively distinguish between Staphylococcus-specific bacteriophages. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessCommunication The Magistral Phage
Viruses 2018, 10(2), 64; https://doi.org/10.3390/v10020064
Received: 15 January 2018 / Revised: 2 February 2018 / Accepted: 3 February 2018 / Published: 6 February 2018
Cited by 15 | PDF Full-text (348 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Since time immemorial, phages—the viral parasites of bacteria—have been protecting Earth’s biosphere against bacterial overgrowth. Today, phages could help address the antibiotic resistance crisis that affects all of society. The greatest hurdle to the introduction of phage therapy in Western medicine is the
[...] Read more.
Since time immemorial, phages—the viral parasites of bacteria—have been protecting Earth’s biosphere against bacterial overgrowth. Today, phages could help address the antibiotic resistance crisis that affects all of society. The greatest hurdle to the introduction of phage therapy in Western medicine is the lack of an appropriate legal and regulatory framework. Belgium is now implementing a pragmatic phage therapy framework that centers on the magistral preparation (compounding pharmacy in the US) of tailor-made phage medicines. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessArticle Characterization of vB_SauM-fRuSau02, a Twort-Like Bacteriophage Isolated from a Therapeutic Phage Cocktail
Viruses 2017, 9(9), 258; https://doi.org/10.3390/v9090258
Received: 29 June 2017 / Revised: 29 August 2017 / Accepted: 11 September 2017 / Published: 14 September 2017
Cited by 3 | PDF Full-text (5329 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Staphylococcus aureus is a commensal and pathogenic bacterium that causes infections in humans and animals. It is a major cause of nosocomial infections worldwide. Due to increasing prevalence of multidrug resistance, alternative methods to eradicate the pathogen are necessary. In this respect, polyvalent
[...] Read more.
Staphylococcus aureus is a commensal and pathogenic bacterium that causes infections in humans and animals. It is a major cause of nosocomial infections worldwide. Due to increasing prevalence of multidrug resistance, alternative methods to eradicate the pathogen are necessary. In this respect, polyvalent staphylococcal myoviruses have been demonstrated to be excellent candidates for phage therapy. Here we present the characterization of the bacteriophage vB_SauM-fRuSau02 (fRuSau02) that was isolated from a commercial Staphylococcus bacteriophage cocktail produced by Microgen (Moscow, Russia). The genomic analysis revealed that fRuSau02 is very closely related to the phage MSA6, and possesses a large genome (148,464 bp), with typical modular organization and a low G+C (30.22%) content. It can therefore be classified as a new virus among the genus Twortlikevirus. The genome contains 236 predicted genes, 4 of which were interrupted by insertion sequences. Altogether, 78 different structural and virion-associated proteins were identified from purified phage particles by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The host range of fRuSau02 was tested with 135 strains, including 51 and 54 Staphylococcus aureus isolates from humans and pigs, respectively, and 30 coagulase-negative Staphylococcus strains of human origin. All clinical S. aureus strains were at least moderately sensitive to the phage, while only 39% of the pig strains were infected. Also, some strains of Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus saprophyticus and Staphylococcus pseudointer were sensitive. We conclude that fRuSau02, a phage therapy agent in Russia, can serve as an alternative to antibiotic therapy against S. aureus. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Review

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Open AccessReview Resistance Development to Bacteriophages Occurring during Bacteriophage Therapy
Viruses 2018, 10(7), 351; https://doi.org/10.3390/v10070351
Received: 10 June 2018 / Revised: 27 June 2018 / Accepted: 28 June 2018 / Published: 30 June 2018
Cited by 1 | PDF Full-text (280 KB) | HTML Full-text | XML Full-text
Abstract
Bacteriophage (phage) therapy, i.e., the use of viruses that infect bacteria as antimicrobial agents, is a promising alternative to conventional antibiotics. Indeed, resistance to antibiotics has become a major public health problem after decades of extensive usage. However, one of the main questions
[...] Read more.
Bacteriophage (phage) therapy, i.e., the use of viruses that infect bacteria as antimicrobial agents, is a promising alternative to conventional antibiotics. Indeed, resistance to antibiotics has become a major public health problem after decades of extensive usage. However, one of the main questions regarding phage therapy is the possible rapid emergence of phage-resistant bacterial variants, which could impede favourable treatment outcomes. Experimental data has shown that phage-resistant variants occurred in up to 80% of studies targeting the intestinal milieu and 50% of studies using sepsis models. Phage-resistant variants have also been observed in human studies, as described in three out of four clinical trials that recorded the emergence of phage resistance. On the other hand, recent animal studies suggest that bacterial mutations that confer phage-resistance may result in fitness costs in the resistant bacterium, which, in turn, could benefit the host. Thus, phage resistance should not be underestimated and efforts should be made to develop methodologies for monitoring and preventing it. Moreover, understanding and taking advantage of the resistance-induced fitness costs in bacterial pathogens is a potentially promising avenue. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
Open AccessReview Delivering Phage Products to Combat Antibiotic Resistance in Developing Countries: Lessons Learned from the HIV/AIDS Epidemic in Africa
Viruses 2018, 10(7), 345; https://doi.org/10.3390/v10070345
Received: 30 May 2018 / Revised: 24 June 2018 / Accepted: 26 June 2018 / Published: 27 June 2018
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Abstract
The antimicrobial resistance (AMR) crisis and HIV/AIDS epidemic exhibit many parallels. In both, infectious diseases have caused millions of deaths worldwide, with AMR expected to kill even more people each year than HIV/AIDS did at its peak. In addition, both have required or
[...] Read more.
The antimicrobial resistance (AMR) crisis and HIV/AIDS epidemic exhibit many parallels. In both, infectious diseases have caused millions of deaths worldwide, with AMR expected to kill even more people each year than HIV/AIDS did at its peak. In addition, both have required or will require new classes of drugs for control. For HIV/AIDS, development of vital antiretroviral drugs (ARVs) was accomplished in several stages: expanding public awareness about the disease, gathering commitment from the international community to tackle the problem, and eventually establishing policies and global funds to deliver new therapeutics. For AMR, the pursuit of new antimicrobials appears to be following a similar trajectory. This paper examines how lessons and processes leading to ARVs might be applied to developing AMR drugs, in particular bacteriophages (phages). These possess many essential characteristics: inexpensive manufacture, rapid drug development, and a ready means to prevent phage-resistant microbes from emerging. However, the broad application of phage-based products has yet to be fully demonstrated, and will require both international coordination and modified regulatory policies. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessReview The Diversity of Bacterial Lifestyles Hampers Bacteriophage Tenacity
Viruses 2018, 10(6), 327; https://doi.org/10.3390/v10060327
Received: 18 May 2018 / Revised: 8 June 2018 / Accepted: 11 June 2018 / Published: 15 June 2018
Cited by 1 | PDF Full-text (488 KB) | HTML Full-text | XML Full-text
Abstract
Phage therapy is based on a simple concept: the use of a virus (bacteriophage) that is capable of killing specific pathogenic bacteria to treat bacterial infections. Since the pioneering work of Félix d’Herelle, bacteriophages (phages) isolated in vitro have been shown to be
[...] Read more.
Phage therapy is based on a simple concept: the use of a virus (bacteriophage) that is capable of killing specific pathogenic bacteria to treat bacterial infections. Since the pioneering work of Félix d’Herelle, bacteriophages (phages) isolated in vitro have been shown to be of therapeutic value. Over decades of study, a large number of rather complex mechanisms that are used by phages to hijack bacterial resources and to produce their progeny have been deciphered. While these mechanisms have been identified and have been studied under optimal conditions in vitro, much less is known about the requirements for successful viral infections in relevant natural conditions. This is particularly true in the context of phage therapy. Here, we highlight the parameters affecting phage replication in both in vitro and in vivo environments, focusing, in particular, on the mammalian digestive tract. We propose avenues for increasing the knowledge-guided implementation of phages as therapeutic tools. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessReview Phage Therapy: What Have We Learned?
Viruses 2018, 10(6), 288; https://doi.org/10.3390/v10060288
Received: 18 April 2018 / Revised: 11 May 2018 / Accepted: 22 May 2018 / Published: 28 May 2018
Cited by 3 | PDF Full-text (369 KB) | HTML Full-text | XML Full-text
Abstract
In this article we explain how current events in the field of phage therapy may positively influence its future development. We discuss the shift in position of the authorities, academia, media, non-governmental organizations, regulatory agencies, patients, and doctors which could enable further advances
[...] Read more.
In this article we explain how current events in the field of phage therapy may positively influence its future development. We discuss the shift in position of the authorities, academia, media, non-governmental organizations, regulatory agencies, patients, and doctors which could enable further advances in the research and application of the therapy. In addition, we discuss methods to obtain optimal phage preparations and suggest the potential of novel applications of phage therapy extending beyond its anti-bacterial action. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessReview Framing the Future with Bacteriophages in Agriculture
Viruses 2018, 10(5), 218; https://doi.org/10.3390/v10050218
Received: 27 March 2018 / Revised: 20 April 2018 / Accepted: 22 April 2018 / Published: 25 April 2018
Cited by 1 | PDF Full-text (289 KB) | HTML Full-text | XML Full-text
Abstract
The ability of agriculture to continually provide food to a growing world population is of crucial importance. Bacterial diseases of plants and animals have continually reduced production since the advent of crop cultivation and animal husbandry practices. Antibiotics have been used extensively to
[...] Read more.
The ability of agriculture to continually provide food to a growing world population is of crucial importance. Bacterial diseases of plants and animals have continually reduced production since the advent of crop cultivation and animal husbandry practices. Antibiotics have been used extensively to mitigate these losses. The rise of antimicrobial resistant (AMR) bacteria, however, together with consumers’ calls for antibiotic-free products, presents problems that threaten sustainable agriculture. Bacteriophages (phages) are proposed as bacterial population control alternatives to antibiotics. Their unique properties make them highly promising but challenging antimicrobials. The use of phages in agriculture also presents a number of unique challenges. This mini-review summarizes recent development and perspectives of phages used as antimicrobial agents in plant and animal agriculture at the farm level. The main pathogens and their adjoining phage therapies are discussed. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
Open AccessReview Bacteriophage Applications for Food Production and Processing
Viruses 2018, 10(4), 205; https://doi.org/10.3390/v10040205
Received: 19 March 2018 / Revised: 10 April 2018 / Accepted: 11 April 2018 / Published: 19 April 2018
Cited by 5 | PDF Full-text (352 KB) | HTML Full-text | XML Full-text
Abstract
Foodborne illnesses remain a major cause of hospitalization and death worldwide despite many advances in food sanitation techniques and pathogen surveillance. Traditional antimicrobial methods, such as pasteurization, high pressure processing, irradiation, and chemical disinfectants are capable of reducing microbial populations in foods to
[...] Read more.
Foodborne illnesses remain a major cause of hospitalization and death worldwide despite many advances in food sanitation techniques and pathogen surveillance. Traditional antimicrobial methods, such as pasteurization, high pressure processing, irradiation, and chemical disinfectants are capable of reducing microbial populations in foods to varying degrees, but they also have considerable drawbacks, such as a large initial investment, potential damage to processing equipment due to their corrosive nature, and a deleterious impact on organoleptic qualities (and possibly the nutritional value) of foods. Perhaps most importantly, these decontamination strategies kill indiscriminately, including many—often beneficial—bacteria that are naturally present in foods. One promising technique that addresses several of these shortcomings is bacteriophage biocontrol, a green and natural method that uses lytic bacteriophages isolated from the environment to specifically target pathogenic bacteria and eliminate them from (or significantly reduce their levels in) foods. Since the initial conception of using bacteriophages on foods, a substantial number of research reports have described the use of bacteriophage biocontrol to target a variety of bacterial pathogens in various foods, ranging from ready-to-eat deli meats to fresh fruits and vegetables, and the number of commercially available products containing bacteriophages approved for use in food safety applications has also been steadily increasing. Though some challenges remain, bacteriophage biocontrol is increasingly recognized as an attractive modality in our arsenal of tools for safely and naturally eliminating pathogenic bacteria from foods. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
Open AccessReview Criteria for Selecting Suitable Infectious Diseases for Phage Therapy
Viruses 2018, 10(4), 177; https://doi.org/10.3390/v10040177
Received: 16 March 2018 / Revised: 30 March 2018 / Accepted: 30 March 2018 / Published: 5 April 2018
Cited by 2 | PDF Full-text (4548 KB) | HTML Full-text | XML Full-text
Abstract
One of the main issues with phage therapy from its earliest days has been the selection of appropriate disease targets. In early work, when the nature of bacteriophages was unknown, many inappropriate targets were selected, including some now known to have no bacterial
[...] Read more.
One of the main issues with phage therapy from its earliest days has been the selection of appropriate disease targets. In early work, when the nature of bacteriophages was unknown, many inappropriate targets were selected, including some now known to have no bacterial involvement whatsoever. More recently, with greatly increased understanding of the highly specific nature of bacteriophages and of their mechanisms of action, it has been possible to select indications with an increased chance of a successful therapeutic outcome. The factors to be considered include the characteristics of the infection to be treated, the characteristics of the bacteria involved, and the characteristics of the bacteriophages themselves. At a later stage all of this information then informs trial design and regulatory considerations. Where the work is undertaken towards the development of a commercial product it is also necessary to consider the planned market, protection of intellectual property, and the sourcing of funding to support the work. It is clear that bacteriophages are not a “magic bullet”. However, with careful and appropriate selection of a limited set of initial targets, it should be possible to obtain proof of concept for the many elements required for the success of phage therapy. In time, success with these initial targets could then support more widespread use. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessReview In Vitro Characteristics of Phages to Guide ‘Real Life’ Phage Therapy Suitability
Viruses 2018, 10(4), 163; https://doi.org/10.3390/v10040163
Received: 14 March 2018 / Revised: 27 March 2018 / Accepted: 29 March 2018 / Published: 30 March 2018
Cited by 2 | PDF Full-text (687 KB) | HTML Full-text | XML Full-text
Abstract
The increasing problem of antibiotic-resistant pathogens has put enormous pressure on healthcare providers to reduce the application of antibiotics and to identify alternative therapies. Phages represent such an alternative with significant application potential, either on their own or in combination with antibiotics to
[...] Read more.
The increasing problem of antibiotic-resistant pathogens has put enormous pressure on healthcare providers to reduce the application of antibiotics and to identify alternative therapies. Phages represent such an alternative with significant application potential, either on their own or in combination with antibiotics to enhance the effectiveness of traditional therapies. However, while phage therapy may offer exciting therapeutic opportunities, its evaluation for safe and appropriate use in humans needs to be guided initially by reliable and appropriate assessment techniques at the laboratory level. Here, we review the process of phage isolation and the application of individual pathogens or reference collections for the development of specific or “off-the-shelf” preparations. Furthermore, we evaluate current characterization approaches to assess the in vitro therapeutic potential of a phage including its spectrum of activity, genome characteristics, storage and administration requirements and effectiveness against biofilms. Lytic characteristics and the ability to overcome anti-phage systems are also covered. These attributes direct phage selection for their ultimate application as antimicrobial agents. We also discuss current pitfalls in this research area and propose that priority should be given to unify current phage characterization approaches. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Other

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Open AccessBrief Report Production of Bacteriophages by Listeria Cells Entrapped in Organic Polymers
Viruses 2018, 10(6), 324; https://doi.org/10.3390/v10060324
Received: 13 May 2018 / Revised: 7 June 2018 / Accepted: 8 June 2018 / Published: 13 June 2018
Cited by 1 | PDF Full-text (1557 KB) | HTML Full-text | XML Full-text
Abstract
Applications for bacteriophages as antimicrobial agents are increasing. The industrial use of these bacterial viruses requires the production of large amounts of suitable strictly lytic phages, particularly for food and agricultural applications. This work describes a new approach for phage production. Phages H387
[...] Read more.
Applications for bacteriophages as antimicrobial agents are increasing. The industrial use of these bacterial viruses requires the production of large amounts of suitable strictly lytic phages, particularly for food and agricultural applications. This work describes a new approach for phage production. Phages H387 (Siphoviridae) and A511 (Myoviridae) were propagated separately using Listeria ivanovii host cells immobilised in alginate beads. The same batch of alginate beads could be used for four successive and efficient phage productions. This technique enables the production of large volumes of high-titer phage lysates in continuous or semi-continuous (fed-batch) cultures. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessComment Phage Therapy Faces Evolutionary Challenges
Viruses 2018, 10(6), 323; https://doi.org/10.3390/v10060323
Received: 18 May 2018 / Revised: 9 June 2018 / Accepted: 12 June 2018 / Published: 12 June 2018
Cited by 1 | PDF Full-text (449 KB) | HTML Full-text | XML Full-text
Abstract
Antibiotic resistance evolution in bacteria indicates that one of the challenges faced by phage therapy is that, sooner or later, bacteria will evolve resistance to phages. Evidently, this is the case of every known antimicrobial therapy, but here this is also part of
[...] Read more.
Antibiotic resistance evolution in bacteria indicates that one of the challenges faced by phage therapy is that, sooner or later, bacteria will evolve resistance to phages. Evidently, this is the case of every known antimicrobial therapy, but here this is also part of a ubiquitous natural process of co-evolution between phages and bacteria. Fundamental evolutionary studies hold some clues that are crucial to limit the problematic process of bacterial resistance during phage applications. First, I discuss here the importance of defining evolutionary and ecological factors influencing bacterial resistance and phage counter-defense mechanisms. Then, I comment on the interest of determining the co-evolutionary dynamics between phages and bacteria that may allow for selecting the conditions that will increase the probability of therapeutic success. I go on to suggest the varied strategies that may ensure the long-term success of phage therapy, including analysis of internal phage parameters and personalized treatments. In practical terms, these types of approaches will define evolutionary criteria regarding how to develop, and when to apply, therapeutic phage cocktails. Integrating this perspective in antimicrobial treatments, such as phage therapy, is among the necessary steps to expand its use in the near future, and to ensure its durability and success. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessComment Phages Make for Jolly Good Stories
Viruses 2018, 10(4), 209; https://doi.org/10.3390/v10040209
Received: 12 March 2018 / Revised: 15 April 2018 / Accepted: 19 April 2018 / Published: 20 April 2018
PDF Full-text (221 KB) | HTML Full-text | XML Full-text
Abstract
Phage therapy has an intriguing history. It was widely used from the 1920s until the 1940s. After this period, it was nearly completely forgotten in the Western world, while it continued to be used in the Soviet part of the globe. The study
[...] Read more.
Phage therapy has an intriguing history. It was widely used from the 1920s until the 1940s. After this period, it was nearly completely forgotten in the Western world, while it continued to be used in the Soviet part of the globe. The study of the history of phage therapy provides valuable input into the present development of the field. Science journalists uncovered much of this history and played an important role in the communication of phage therapy after the fall of the Soviet Union, when it came to the attention of Western researchers and doctors. This interest was fueled by the antibiotic resistance crisis. At this time, communication about phage therapy had a wide potential audience, that encompassed medical experts and researchers, as well as the public, because knowledge about this forgotten therapy was very limited. In such a situation, good communication had and still has the potential to catalyze important discussions among different groups; whereas, bad communication could have considerably hindered and still can hinder the possible renaissance of phage therapy. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
Open AccessConference Report Expert Opinion on Three Phage Therapy Related Topics: Bacterial Phage Resistance, Phage Training and Prophages in Bacterial Production Strains
Viruses 2018, 10(4), 178; https://doi.org/10.3390/v10040178
Received: 31 March 2018 / Revised: 3 April 2018 / Accepted: 3 April 2018 / Published: 5 April 2018
Cited by 5 | PDF Full-text (322 KB) | HTML Full-text | XML Full-text
Abstract
Phage therapy is increasingly put forward as a “new” potential tool in the fight against antibiotic resistant infections. During the “Centennial Celebration of Bacteriophage Research” conference in Tbilisi, Georgia on 26–29 June 2017, an international group of phage researchers committed to elaborate an
[...] Read more.
Phage therapy is increasingly put forward as a “new” potential tool in the fight against antibiotic resistant infections. During the “Centennial Celebration of Bacteriophage Research” conference in Tbilisi, Georgia on 26–29 June 2017, an international group of phage researchers committed to elaborate an expert opinion on three contentious phage therapy related issues that are hampering clinical progress in the field of phage therapy. This paper explores and discusses bacterial phage resistance, phage training and the presence of prophages in bacterial production strains while reviewing relevant research findings and experiences. Our purpose is to inform phage therapy stakeholders such as policy makers, officials of the competent authorities for medicines, phage researchers and phage producers, and members of the pharmaceutical industry. This brief also points out potential avenues for future phage therapy research and development as it specifically addresses those overarching questions that currently call for attention whenever phages go into purification processes for application. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
Open AccessBrief Report Selection of Potential Therapeutic Bacteriophages that Lyse a CTX-M-15 Extended Spectrum β-Lactamase Producing Salmonella enterica Serovar Typhi Strain from the Democratic Republic of the Congo
Viruses 2018, 10(4), 172; https://doi.org/10.3390/v10040172
Received: 9 March 2018 / Revised: 31 March 2018 / Accepted: 2 April 2018 / Published: 3 April 2018
Cited by 2 | PDF Full-text (4060 KB) | HTML Full-text | XML Full-text
Abstract
Recently, a Salmonella Typhi isolate producing CTX-M-15 extended spectrum β-lactamase (ESBL) and with decreased ciprofloxacin susceptibility was isolated in the Democratic Republic of the Congo. We have selected bacteriophages that show strong lytic activity against this isolate and have potential for phage-based treatment
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Recently, a Salmonella Typhi isolate producing CTX-M-15 extended spectrum β-lactamase (ESBL) and with decreased ciprofloxacin susceptibility was isolated in the Democratic Republic of the Congo. We have selected bacteriophages that show strong lytic activity against this isolate and have potential for phage-based treatment of S. Typhi, and Salmonella in general. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessConference Report 1st German Phage Symposium—Conference Report
Viruses 2018, 10(4), 158; https://doi.org/10.3390/v10040158
Received: 13 March 2018 / Revised: 23 March 2018 / Accepted: 25 March 2018 / Published: 29 March 2018
Cited by 1 | PDF Full-text (373 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In Germany, phage research and application can be traced back to the beginning of the 20th century. However, with the triumphal march of antibiotics around the world, the significance of bacteriophages faded in most countries, and respective research mainly focused on fundamental questions
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In Germany, phage research and application can be traced back to the beginning of the 20th century. However, with the triumphal march of antibiotics around the world, the significance of bacteriophages faded in most countries, and respective research mainly focused on fundamental questions and niche applications. After a century, we pay tribute to the overuse of antibiotics that led to multidrug resistance and calls for new strategies to combat pathogenic microbes. Against this background, bacteriophages came into the spotlight of researchers and practitioners again resulting in a fast growing “phage community”. In October 2017, part of this community met at the 1st German Phage Symposium to share their knowledge and experiences. The participants discussed open questions and challenges related to phage therapy and the application of phages in general. This report summarizes the presentations given, highlights the main points of the round table discussion and concludes with an outlook for the different aspects of phage application. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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