Special Issue "Bacteriophages: Alternatives to Antibiotics and Beyond"

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: 31 January 2019

Special Issue Editor

Guest Editor
Dr. Pilar García Suárez

Instituto de Productos Lácteos de Asturias (IPLA-CSIC), 33300 Villaviciosa, Asturias, Spain
Website | E-Mail
Interests: bacteriophages; biocontrol

Special Issue Information

Dear Colleagues,

The quick rise in multi-drug resistance detected among bacterial pathogens is compromising the control of these microorganisms in several areas related to human health. For some years now, we have been witnessing with concern the arrival of the post-antibiotic era and looking for alternatives to fight against resistant bacteria. The use of bacteriophages (phage therapy) arises as a feasible alternative, which had already been partially explored a century ago. Currently, many studies confirm the efficacy of this therapy but there are still some controversies mainly regarding its safety. Therefore, the main subject of this Special Issue includes any bacteriophage-based approach to control bacteria in areas such as human and veterinary medicine, food industry, agriculture, natural environments, etc. In addition, manuscripts concerning other phage-related areas of interest are welcome:

  1. New phage lytic proteins and engineered derivatives.
  2. Phage genome mining and study of unknown genes.
  3. Bacterial host resistance, virulence transmission and/or induction, phage-host interaction and evolution.
  4. Specific bacteria detection methods using phage-based tools.
  5. Phage and phage protein delivery in animal models of infection.
  6. Pharmacodynamics of phages and phage proteins.
  7. Large scale production of bacteriophages and phage proteins.
  8. Regulatory framework for the use of phages and phage proteins in human and animal medicine.
  9. Phages as biocontrol agents in natural and man-made environments.

Dr. Pilar García Suárez
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. Antibiotics 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 550 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

  • Bacteriophages
  • Endolysins
  • virion-associate peptidoglycan hydrolases
  • phage therapy
  • phage biocontrol
  • bacteriophage resistance

Published Papers (14 papers)

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Research

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Open AccessArticle Exploring the Effect of Phage Therapy in Preventing Vibrio anguillarum Infections in Cod and Turbot Larvae
Antibiotics 2018, 7(2), 42; https://doi.org/10.3390/antibiotics7020042
Received: 30 December 2017 / Revised: 1 May 2018 / Accepted: 10 May 2018 / Published: 16 May 2018
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Abstract
The aquaculture industry is suffering from losses associated with bacterial infections by opportunistic pathogens. Vibrio anguillarum is one of the most important pathogens, causing vibriosis in fish and shellfish cultures leading to high mortalities and economic losses. Bacterial resistance to antibiotics and inefficient
[...] Read more.
The aquaculture industry is suffering from losses associated with bacterial infections by opportunistic pathogens. Vibrio anguillarum is one of the most important pathogens, causing vibriosis in fish and shellfish cultures leading to high mortalities and economic losses. Bacterial resistance to antibiotics and inefficient vaccination at the larval stage of fish emphasizes the need for novel approaches, and phage therapy for controlling Vibrio pathogens has gained interest in the past few years. In this study, we examined the potential of the broad-host-range phage KVP40 to control four different V. anguillarum strains in Atlantic cod (Gadus morhua L.) and turbot (Scophthalmus maximus L.) larvae. We examined larval mortality and abundance of bacteria and phages. Phage KVP40 was able to reduce and/or delay the mortality of the cod and turbot larvae challenged with V. anguillarum. However, growth of other pathogenic bacteria naturally occurring on the fish eggs prior to our experiment caused mortality of the larvae in the unchallenged control groups. Interestingly, the broad-spectrum phage KVP40 was able to reduce mortality in these groups, compared to the nonchallenge control groups not treated with phage KVP40, demonstrating that the phage could also reduce mortality imposed by the background population of pathogens. Overall, phage-mediated reduction in mortality of cod and turbot larvae in experimental challenge assays with V. anguillarum pathogens suggested that application of broad-host-range phages can reduce Vibrio-induced mortality in turbot and cod larvae, emphasizing that phage therapy is a promising alternative to traditional treatment of vibriosis in marine aquaculture. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessArticle Comparison of Staphylococcus Phage K with Close Phage Relatives Commonly Employed in Phage Therapeutics
Antibiotics 2018, 7(2), 37; https://doi.org/10.3390/antibiotics7020037
Received: 9 March 2018 / Revised: 12 April 2018 / Accepted: 19 April 2018 / Published: 25 April 2018
PDF Full-text (1358 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The increase in antibiotic resistance in pathogenic bacteria is a public health danger requiring alternative treatment options, and this has led to renewed interest in phage therapy. In this respect, we describe the distinct host ranges of Staphylococcus phage K, and two other
[...] Read more.
The increase in antibiotic resistance in pathogenic bacteria is a public health danger requiring alternative treatment options, and this has led to renewed interest in phage therapy. In this respect, we describe the distinct host ranges of Staphylococcus phage K, and two other K-like phages against 23 isolates, including 21 methicillin-resistant S. aureus (MRSA) representative sequence types representing the Irish National MRSA Reference Laboratory collection. The two K-like phages were isolated from the Fersisi therapeutic phage mix from the Tbilisi Eliava Institute, and were designated B1 (vB_SauM_B1) and JA1 (vB_SauM_JA1). The sequence relatedness of B1 and JA1 to phage K was observed to be 95% and 94% respectively. In terms of host range on the 23 Staphylococcus isolates, B1 and JA1 infected 73.9% and 78.2% respectively, whereas K infected only 43.5%. Eleven open reading frames (ORFs) present in both phages B1 and JA1 but absent in phage K were identified by comparative genomic analysis. These ORFs were also found to be present in the genomes of phages (Team 1, vB_SauM-fRuSau02, Sb_1 and ISP) that are components of several commercial phage mixtures with reported wide host ranges. This is the first comparative study of therapeutic staphylococcal phages within the recently described genus Kayvirus. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessArticle Protein Expression Modifications in Phage-Resistant Mutants of Aeromonas salmonicida after AS-A Phage Treatment
Antibiotics 2018, 7(1), 21; https://doi.org/10.3390/antibiotics7010021
Received: 31 January 2018 / Revised: 1 March 2018 / Accepted: 6 March 2018 / Published: 8 March 2018
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Abstract
The occurrence of infections by pathogenic bacteria is one of the main sources of financial loss for the aquaculture industry. This problem often cannot be solved with antibiotic treatment or vaccination. Phage therapy seems to be an alternative environmentally-friendly strategy to control infections.
[...] Read more.
The occurrence of infections by pathogenic bacteria is one of the main sources of financial loss for the aquaculture industry. This problem often cannot be solved with antibiotic treatment or vaccination. Phage therapy seems to be an alternative environmentally-friendly strategy to control infections. Recognizing the cellular modifications that bacteriophage therapy may cause to the host is essential in order to confirm microbial inactivation, while understanding the mechanisms that drive the development of phage-resistant strains. The aim of this work was to detect cellular modifications that occur after phage AS-A treatment in A. salmonicida, an important fish pathogen. Phage-resistant and susceptible cells were subjected to five successive streak-plating steps and analysed with infrared spectroscopy, a fast and powerful tool for cell study. The spectral differences of both populations were investigated and compared with a phage sensitivity profile, obtained through the spot test and efficiency of plating. Changes in protein associated peaks were found, and these results were corroborated by 1-D electrophoresis of intracellular proteins analysis and by phage sensitivity profiles. Phage AS-A treatment before the first streaking-plate step clearly affected the intracellular proteins expression levels of phage-resistant clones, altering the expression of distinct proteins during the subsequent five successive streak-plating steps, making these clones recover and be phenotypically more similar to the sensitive cells. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessArticle Protective Effects of Bacteriophages against Aeromonas hydrophila Causing Motile Aeromonas Septicemia (MAS) in Striped Catfish
Antibiotics 2018, 7(1), 16; https://doi.org/10.3390/antibiotics7010016
Received: 28 December 2017 / Revised: 30 January 2018 / Accepted: 23 February 2018 / Published: 25 February 2018
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Abstract
To determine the effectivity of bacteriophages in controlling the mass mortality of striped catfish (Pangasianodon hypophthalmus) due to infections caused by Aeromonas spp. in Vietnamese fish farms, bacteriophages against pathogenic Aeromonas hydrophila were isolated. A. hydrophila-phage 2 and A. hydrophila
[...] Read more.
To determine the effectivity of bacteriophages in controlling the mass mortality of striped catfish (Pangasianodon hypophthalmus) due to infections caused by Aeromonas spp. in Vietnamese fish farms, bacteriophages against pathogenic Aeromonas hydrophila were isolated. A. hydrophila-phage 2 and A. hydrophila-phage 5 were successfully isolated from water samples from the Saigon River of Ho Chi Minh City, Vietnam. These phages, belonging to the Myoviridae family, were found to have broad activity spectra, even against the tested multiple-antibiotic-resistant Aeromonas isolates. The latent periods and burst size of phage 2 were 10 min and 213 PFU per infected host cell, respectively. The bacteriophages proved to be effective in inhibiting the growth of the Aeromonas spp. under laboratory conditions. Phage treatments applied to the pathogenic strains during infestation of catfish resulted in a significant improvement in the survival rates of the tested fishes, with up to 100% survival with MOI 100, compared to 18.3% survival observed in control experiments. These findings illustrate the potential for using phages as an effective bio-treatment method to control Motile Aeromonas Septicemia (MAS) in fish farms. This study provides further evidence towards the use of bacteriophages to effectively control disease in aquaculture operations. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessArticle Efficacy of an Optimised Bacteriophage Cocktail to Clear Clostridium difficile in a Batch Fermentation Model
Antibiotics 2018, 7(1), 13; https://doi.org/10.3390/antibiotics7010013
Received: 31 December 2017 / Revised: 3 February 2018 / Accepted: 6 February 2018 / Published: 13 February 2018
Cited by 4 | PDF Full-text (4649 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Clostridium difficile infection (CDI) is a major cause of infectious diarrhea. Conventional antibiotics are not universally effective for all ribotypes, and can trigger dysbiosis, resistance and recurrent infection. Thus, novel therapeutics are needed to replace and/or supplement the current antibiotics. Here, we describe
[...] Read more.
Clostridium difficile infection (CDI) is a major cause of infectious diarrhea. Conventional antibiotics are not universally effective for all ribotypes, and can trigger dysbiosis, resistance and recurrent infection. Thus, novel therapeutics are needed to replace and/or supplement the current antibiotics. Here, we describe the activity of an optimised 4-phage cocktail to clear cultures of a clinical ribotype 014/020 strain in fermentation vessels spiked with combined fecal slurries from four healthy volunteers. After 5 h, we observed ~6-log reductions in C. difficile abundance in the prophylaxis regimen and complete C. difficile eradication after 24 h following prophylactic or remedial regimens. Viability assays revealed that commensal enterococci, bifidobacteria, lactobacilli, total anaerobes, and enterobacteria were not affected by either regimens, but a ~2-log increase in the enterobacteria, lactobacilli, and total anaerobe abundance was seen in the phage-only-treated vessel compared to other treatments. The impact of the phage treatments on components of the microbiota was further assayed using metagenomic analysis. Together, our data supports the therapeutic application of our optimised phage cocktail to treat CDI. Also, the increase in specific commensals observed in the phage-treated control could prevent further colonisation of C. difficile, and thus provide protection from infection being able to establish. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessArticle Use of a Regression Model to Study Host-Genomic Determinants of Phage Susceptibility in MRSA
Received: 15 November 2017 / Revised: 20 January 2018 / Accepted: 24 January 2018 / Published: 29 January 2018
Cited by 1 | PDF Full-text (1965 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Staphylococcus aureus is a major agent of nosocomial infections. Especially in methicillin-resistant strains, conventional treatment options are limited and expensive, which has fueled a growing interest in phage therapy approaches. We have tested the susceptibility of 207 clinical S. aureus strains to 12
[...] Read more.
Staphylococcus aureus is a major agent of nosocomial infections. Especially in methicillin-resistant strains, conventional treatment options are limited and expensive, which has fueled a growing interest in phage therapy approaches. We have tested the susceptibility of 207 clinical S. aureus strains to 12 (nine monovalent) different therapeutic phage preparations and subsequently employed linear regression models to estimate the influence of individual host gene families on resistance to phages. Specifically, we used a two-step regression model setup with a preselection step based on gene family enrichment. We show that our models are robust and capture the data’s underlying signal by comparing their performance to that of models build on randomized data. In doing so, we have identified 167 gene families that govern phage resistance in our strain set and performed functional analysis on them. This revealed genes of possible prophage or mobile genetic element origin, along with genes involved in restriction-modification and transcription regulators, though the majority were genes of unknown function. This study is a step in the direction of understanding the intricate host-phage relationship in this important pathogen with the outlook to targeted phage therapy applications. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessArticle Phage-Bacterial Dynamics with Spatial Structure: Self Organization around Phage Sinks Can Promote Increased Cell Densities
Received: 27 December 2017 / Revised: 21 January 2018 / Accepted: 23 January 2018 / Published: 29 January 2018
Cited by 1 | PDF Full-text (1303 KB) | HTML Full-text | XML Full-text
Abstract
Bacteria growing on surfaces appear to be profoundly more resistant to control by lytic bacteriophages than do the same cells grown in liquid. Here, we use simulation models to investigate whether spatial structure per se can account for this increased cell density in
[...] Read more.
Bacteria growing on surfaces appear to be profoundly more resistant to control by lytic bacteriophages than do the same cells grown in liquid. Here, we use simulation models to investigate whether spatial structure per se can account for this increased cell density in the presence of phages. A measure is derived for comparing cell densities between growth in spatially structured environments versus well mixed environments (known as mass action). Maintenance of sensitive cells requires some form of phage death; we invoke death mechanisms that are spatially fixed, as if produced by cells. Spatially structured phage death provides cells with a means of protection that can boost cell densities an order of magnitude above that attained under mass action, although the effect is sometimes in the opposite direction. Phage and bacteria self organize into separate refuges, and spatial structure operates so that the phage progeny from a single burst do not have independent fates (as they do with mass action). Phage incur a high loss when invading protected areas that have high cell densities, resulting in greater protection for the cells. By the same metric, mass action dynamics either show no sustained bacterial elevation or oscillate between states of low and high cell densities and an elevated average. The elevated cell densities observed in models with spatial structure do not approach the empirically observed increased density of cells in structured environments with phages (which can be many orders of magnitude), so the empirical phenomenon likely requires additional mechanisms than those analyzed here. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Review

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Open AccessReview Bacteriophages: Protagonists of a Post-Antibiotic Era
Antibiotics 2018, 7(3), 66; https://doi.org/10.3390/antibiotics7030066
Received: 12 July 2018 / Revised: 24 July 2018 / Accepted: 25 July 2018 / Published: 27 July 2018
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Abstract
Despite their long success for more than half a century, antibiotics are currently under the spotlight due to the emergence of multidrug-resistant bacteria. The development of new alternative treatments is of particular interest in the fight against bacterial resistance. Bacteriophages (phages) are natural
[...] Read more.
Despite their long success for more than half a century, antibiotics are currently under the spotlight due to the emergence of multidrug-resistant bacteria. The development of new alternative treatments is of particular interest in the fight against bacterial resistance. Bacteriophages (phages) are natural killers of bacteria and are an excellent tool due to their specificity and ecological safety. Here, we highlight some of their advantages and drawbacks as potential therapeutic agents. Interestingly, phages are not only attractive from a clinical point of view, but other areas, such as agriculture, food control, or industry, are also areas for their potential application. Therefore, we propose phages as a real alternative to current antibiotics. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessReview Engineering of Phage-Derived Lytic Enzymes: Improving Their Potential as Antimicrobials
Antibiotics 2018, 7(2), 29; https://doi.org/10.3390/antibiotics7020029
Received: 2 February 2018 / Revised: 16 March 2018 / Accepted: 20 March 2018 / Published: 22 March 2018
Cited by 5 | PDF Full-text (1122 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Lytic enzymes encoded by bacteriophages have been intensively explored as alternative agents for combating bacterial pathogens in different contexts. The antibacterial character of these enzymes (enzybiotics) results from their degrading activity towards peptidoglycan, an essential component of the bacterial cell wall. In fact,
[...] Read more.
Lytic enzymes encoded by bacteriophages have been intensively explored as alternative agents for combating bacterial pathogens in different contexts. The antibacterial character of these enzymes (enzybiotics) results from their degrading activity towards peptidoglycan, an essential component of the bacterial cell wall. In fact, phage lytic products have the capacity to kill target bacteria when added exogenously in the form of recombinant proteins. However, there is also growing recognition that the natural bactericidal activity of these agents can, and sometimes needs to be, substantially improved through manipulation of their functional domains or by equipping them with new functions. In addition, often, native lytic proteins exhibit features that restrict their applicability as effective antibacterials, such as poor solubility or reduced stability. Here, I present an overview of the engineering approaches that can be followed not only to overcome these and other restrictions, but also to generate completely new antibacterial agents with significantly enhanced characteristics. As conventional antibiotics are running short, the remarkable progress in this field opens up the possibility of tailoring efficient enzybiotics to tackle the most menacing bacterial infections. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessReview Potential for Bacteriophage Endolysins to Supplement or Replace Antibiotics in Food Production and Clinical Care
Antibiotics 2018, 7(1), 17; https://doi.org/10.3390/antibiotics7010017
Received: 21 December 2017 / Revised: 6 February 2018 / Accepted: 23 February 2018 / Published: 27 February 2018
Cited by 3 | PDF Full-text (902 KB) | HTML Full-text | XML Full-text
Abstract
There is growing concern about the emergence of bacterial strains showing resistance to all classes of antibiotics commonly used in human medicine. Despite the broad range of available antibiotics, bacterial resistance has been identified for every antimicrobial drug developed to date. Alarmingly, there
[...] Read more.
There is growing concern about the emergence of bacterial strains showing resistance to all classes of antibiotics commonly used in human medicine. Despite the broad range of available antibiotics, bacterial resistance has been identified for every antimicrobial drug developed to date. Alarmingly, there is also an increasing prevalence of multidrug-resistant bacterial strains, rendering some patients effectively untreatable. Therefore, there is an urgent need to develop alternatives to conventional antibiotics for use in the treatment of both humans and food-producing animals. Bacteriophage-encoded lytic enzymes (endolysins), which degrade the cell wall of the bacterial host to release progeny virions, are potential alternatives to antibiotics. Preliminary studies show that endolysins can disrupt the cell wall when applied exogenously, though this has so far proven more effective in Gram-positive bacteria compared with Gram-negative bacteria. Their potential for development is furthered by the prospect of bioengineering, and aided by the modular domain structure of many endolysins, which separates the binding and catalytic activities into distinct subunits. These subunits can be rearranged to create novel, chimeric enzymes with optimized functionality. Furthermore, there is evidence that the development of resistance to these enzymes may be more difficult compared with conventional antibiotics due to their targeting of highly conserved bonds. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessReview Bacteriophage Interactions with Marine Pathogenic Vibrios: Implications for Phage Therapy
Antibiotics 2018, 7(1), 15; https://doi.org/10.3390/antibiotics7010015
Received: 1 February 2018 / Revised: 19 February 2018 / Accepted: 21 February 2018 / Published: 24 February 2018
Cited by 2 | PDF Full-text (1810 KB) | HTML Full-text | XML Full-text
Abstract
A global distribution in marine, brackish, and freshwater ecosystems, in combination with high abundances and biomass, make vibrios key players in aquatic environments, as well as important pathogens for humans and marine animals. Incidents of Vibrio-associated diseases (vibriosis) in marine aquaculture are
[...] Read more.
A global distribution in marine, brackish, and freshwater ecosystems, in combination with high abundances and biomass, make vibrios key players in aquatic environments, as well as important pathogens for humans and marine animals. Incidents of Vibrio-associated diseases (vibriosis) in marine aquaculture are being increasingly reported on a global scale, due to the fast growth of the industry over the past few decades years. The administration of antibiotics has been the most commonly applied therapy used to control vibriosis outbreaks, giving rise to concerns about development and spreading of antibiotic-resistant bacteria in the environment. Hence, the idea of using lytic bacteriophages as therapeutic agents against bacterial diseases has been revived during the last years. Bacteriophage therapy constitutes a promising alternative not only for treatment, but also for prevention of vibriosis in aquaculture. However, several scientific and technological challenges still need further investigation before reliable, reproducible treatments with commercial potential are available for the aquaculture industry. The potential and the challenges of phage-based alternatives to antibiotic treatment of vibriosis are addressed in this review. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessFeature PaperReview Bacteriophages in the Dairy Environment: From Enemies to Allies
Antibiotics 2017, 6(4), 27; https://doi.org/10.3390/antibiotics6040027
Received: 5 October 2017 / Revised: 3 November 2017 / Accepted: 6 November 2017 / Published: 8 November 2017
Cited by 3 | PDF Full-text (1038 KB) | HTML Full-text | XML Full-text
Abstract
The history of dairy farming goes back thousands of years, evolving from a traditional small-scale production to the industrialized manufacturing of fermented dairy products. Commercialization of milk and its derived products has been very important not only as a source of nourishment but
[...] Read more.
The history of dairy farming goes back thousands of years, evolving from a traditional small-scale production to the industrialized manufacturing of fermented dairy products. Commercialization of milk and its derived products has been very important not only as a source of nourishment but also as an economic resource. However, the dairy industry has encountered several problems that have to be overcome to ensure the quality and safety of the final products, as well as to avoid economic losses. Within this context, it is interesting to highlight the role played by bacteriophages, or phages, viruses that infect bacteria. Indeed, bacteriophages were originally regarded as a nuisance, being responsible for fermentation failure and economic losses when infecting lactic acid bacteria, but are now considered promising antimicrobials to fight milk-borne pathogens without contributing to the increase in antibiotic resistance. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Other

Jump to: Research, Review

Open AccessPerspective Silk Route to the Acceptance and Re-Implementation of Bacteriophage Therapy—Part II
Antibiotics 2018, 7(2), 35; https://doi.org/10.3390/antibiotics7020035
Received: 25 March 2018 / Revised: 12 April 2018 / Accepted: 12 April 2018 / Published: 23 April 2018
Cited by 2 | PDF Full-text (337 KB) | HTML Full-text | XML Full-text
Abstract
This perspective paper follows up on earlier communications on bacteriophage therapy that we wrote as a multidisciplinary and intercontinental expert-panel when we first met at a bacteriophage conference hosted by the Eliava Institute in Tbilisi, Georgia in 2015. In the context of a
[...] Read more.
This perspective paper follows up on earlier communications on bacteriophage therapy that we wrote as a multidisciplinary and intercontinental expert-panel when we first met at a bacteriophage conference hosted by the Eliava Institute in Tbilisi, Georgia in 2015. In the context of a society that is confronted with an ever-increasing number of antibiotic-resistant bacteria, we build on the previously made recommendations and specifically address how the Nagoya Protocol might impact the further development of bacteriophage therapy. By reviewing a number of recently conducted case studies with bacteriophages involving patients with bacterial infections that could no longer be successfully treated by regular antibiotic therapy, we again stress the urgency and significance of the development of international guidelines and frameworks that might facilitate the legal and effective application of bacteriophage therapy by physicians and the receiving patients. Additionally, we list and comment on several recently started and ongoing clinical studies, including highly desired double-blind placebo-controlled randomized clinical trials. We conclude with an outlook on how recently developed DNA editing technologies are expected to further control and enhance the efficient application of bacteriophages. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
Open AccessOpinion Is Genetic Mobilization Considered When Using Bacteriophages in Antimicrobial Therapy?
Antibiotics 2017, 6(4), 32; https://doi.org/10.3390/antibiotics6040032
Received: 5 September 2017 / Revised: 15 November 2017 / Accepted: 4 December 2017 / Published: 5 December 2017
Cited by 1 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
Abstract
The emergence of multi-drug resistant bacteria has undermined our capacity to control bacterial infectious diseases. Measures needed to tackle this problem include controlling the spread of antibiotic resistance, designing new antibiotics, and encouraging the use of alternative therapies. Phage therapy seems to be
[...] Read more.
The emergence of multi-drug resistant bacteria has undermined our capacity to control bacterial infectious diseases. Measures needed to tackle this problem include controlling the spread of antibiotic resistance, designing new antibiotics, and encouraging the use of alternative therapies. Phage therapy seems to be a feasible alternative to antibiotics, although there are still some concerns and legal issues to overcome before it can be implemented on a large scale. Here we highlight some of those concerns, especially those related to the ability of bacteriophages to transport bacterial DNA and, in particular, antibiotic resistance genes. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title:
Bacteriophages in the Dairy Environment: From Enemies to Allies
Authors:
Lucía Fernández, Susana Escobedo, Diana Gutiérrez, Silvia Portilla, Beatriz Martínez, Pilar García and Ana Rodríguez
Abstract:
The history of dairy farming goes back thousands of years, evolving from a traditional small-scale production to the industrialized manufacturing of fermented dairy products. Commercialization of milk and its derived products has been very important not only as a source of nourishment but also as an economic resource. However, the dairy industry has encountered several problems that have to be overcome to ensure the quality and safety of the final products, as well as to avoid economic losses. Within this context, it is interesting to highlight the role played by bacteriophages, or phages, viruses that infect bacteria. Indeed, bacteriophages were originally regarded as a nuisance, being responsible for fermentation failure and economic losses when infecting lactic acid bacteria, but are now considered promising antimicrobials to fight milk-borne pathogens without contributing to the increase in antibiotic resistance.
Keywords: bacteriophages; dairy industry; pathogens; lactic acid bacteria; fermentation failure; biofilms; antimicrobial resistance

Authors: Paul E. Turner and Benjamin Chan
Affiliation: Yale University, New Haven, CT 06520, USA
Title: Phage and antibiotics synergistically break down Pseudomonas aeruginosa biofilms on prosthetic materials
Summary: In this study, we present data that lytic phage OMKO1 plus either of two antibiotics (ceftazadime, ciprofloxacin) act synergistically to break down biofilms of Pseudomonas aeruginosa on four prosthetic materials (Dacron, felt, Gore-tex, polypropylene), relative to use of antibiotic or phage alone. These results relate to our use of the phage in experimental treatment of a volunteer patient (case-study manuscript currently under review), and in development of the phage for clinical trials under consideration by the U.S. Food & Drug Administration.

Title: Detection of Escherichia coli in ready-to-eat fresh vegetables using broad-host-range recombinant phages
Authors: Hoang A. Hoang1,*, and Kiyohiko Nakasaki2
Affiliation:
1Department of Biotechnology, Faculty of Chemical Engineering, Ho Chi Minh City University of Technology, 268 Ly Thuong Kiet, District 10, Ho Chi Minh city, Vietnam
2Department of International Development Engineering, Tokyo Institute of Technology, Japan
*Corresponding author:
Hoang A. Hoang, Ph.D.
Department of Biotechnology, Faculty of Chemical Engineering, Ho Chi Minh City University of Technology, 268 Ly Thuong Kiet, District 10, Ho Chi Minh city, Vietnam
Tel.: +84-8-38639341; Email: hoang.a.hoang@hcmut.edu.vn
Keywords: Escherichia coli; bacteriophage; vegetables; fecal contamination indicator; detection.
Abstract: Escherichia coli has been used as an indicator of fecal contamination in food samples in many countries. In this study, a method for the colorimetric detection of E. coli in ready-to-eat fresh vegetables using broad-host-range recombinant phages was investigated. Firstly, a gene encoding Cytochrome c Peroxidase (CCP) chromogenic enzyme was inserted into genomes of wild-type phages IP008 and IP052 resulting in the recombinant phages IP008BK and IP052BK. They were used in the production of the chromogenic enzyme through infection into E. coli. The method was then examined in the colorimetric detection of E. coli K12 in broth, and the appearance of E. coli K12 in broth was confirmed by a significant absorbance change after a few minutes of the enzyme assay. Secondly, the protocol using the recombinant phages for detection of E. coli in vegetables, i.e. lettuce and mustard greens was investigated. A low E. coli concentration as 4 CFU g-1 vegetable was detected within 16.5 hours that was in a shorter time than agar-plate methods and some previous phage-based methods. Moreover, the method is simple and convenient since it enables detection without the need for expensive apparatus.

Title: Potential for bacteriophage endolysins to replace antibiotics in food production and clinical care
Authors: Michael Love1, Renwick Dobson2 and Craig Billington1,2*
Affiliation:
1 Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand;
2 Institute of Environmental Science and Research, Christchurch, New Zealand;
Abstract: There is growing concern about the emergence of bacteria resistant to antibiotics used for treatment of human diseases. There are currently no antibiotics used for human medicine for which resistant bacteria have not been isolated. Of concern is the increased prevalence of bacteria which are resistant to multiple antibiotics, which means some patients are unable to be treated with any antibiotic. So there is an urgent need to develop alternatives to conventional antibiotics which can be used for the treatment of humans and animals used for food production. Bacteriophage encoded lytic enzymes (endolysins), which degrade the cell wall of bacteria from within at the end of the bacteriophage life cycle, could be used for this purpose. This is made possible by the observation that endolysins can disrupt the cell wall when applied exogenously, though this has so far proven more effective for gram-positive than gram-negative microorganisms. Endolysins can degrade the cell wall by cleaving a variety of bonds in the glycan backbone or peptide crosslinks and generally have a modular or globular domain structure. There is evidence that resistance to these enzymes may be more difficult to develop compared to conventional antibiotics due to the targeting of highly conserved bonds.

Title: Potential of Phage Therapy in Preventing Vibrio anguillarum Infections in Cod and Turbot Larvae
Authors:
Nanna Rørbo 1, Anita Rønneseth 2, Panos G. Kalatzis 1, Bastian Barker Rasmussen 3, Kirsten Engell-Sørensen 4, Hans Petter Kleppen 5, Heidrun Inger Wergeland 2, Lone Gram 3 and Mathias Middelboe 1
Affiliation:
1  Marine Biological Section, University of Copenhagen, Helsingør, Denmark
2  Department of Biology, University of Bergen, Bergen, Norway
3  Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
4  Fishlab, Højbjerg, Denmark
5 ACD Pharmaceuticals AS, Oslo, Norway
Abstract: The aquaculture industry is suffering fromlosses associated with bacterial infections by opportunistic pathogens. Vibrio anguillarum is one of the most important of the pathogens, causing vibrios is fish and shellfish cultures leading to high mortalities and economic losses. Bacterial resistance to antibiotics inefficient vaccination at the larval stage of fish, emphasizes the need for novel approaches, and phage therapy for controlling Vibrio pathogens has gained interest the past few years.In this study, we examined the potential of the broad-host-range phage, KVP40, to control four different V. anguillarum strains during exposure to cod and turbot larvae by examination of larval mortality and abundance of bacteria and phages. Phage KVP40 was able to reduce and/or delay the mortality of the cod and turbot larvae challenged with V. anguillarum, emphasizing the potential of phage KVP40 to control the added V. anguillarum pathogens. During incubation, however, growth of other pathogenic bacteria associated with the fish eggs prior to incubations caused mortality of the larvae. Interestingly, the addition of phages reduced larval mortality relative to the non-challenged controls (without addition of phage or V. anguillarum), demonstrating that the phage could also reduce mortality imposed by the background population of pathogens. Overall, phage-mediated reduction in mortality of cod and turbot larvae in experimental challenges assays with Vibrio anguillarum pathogens suggested that application of broad host range phages can reduce Vibrio-induced mortality in turbot and cod larvae, emphasizing that phage therapy is a promising alternative to traditional treatment of vibriosis in marine aquaculture.

Title: Engineering of Phage-Derived Lytic Enzymes: Improving Their Potential as Antimicrobials
Author: Carlos São-José
Affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
Abstract: Lytic enzymes encoded by bacteriophages have been intensively explored as alternative agents for the combat of bacterial pathogens in different contexts. The antibacterial character of these enzymes results from their degrading activity towards peptidoglycan, an essential component of the bacterial cell wall. Very often however, the native lytic proteins exhibit features that restrict their applicability as effective antibacterials, such as poor solubility or reduced lytic efficacy. Here I briefly present an overview of the engineering approaches that have been followed not only to overcome these and other restrictions, but also to generate completely new antibacterial agents with significantly improved properties.
Keywords: Endolysin; lysin; lytic enzyme; peptidoglycan hydrolase; antimicrobial; antibacterial; antibiotic resistance; antimicrobial resistance; bacteriophage

 

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