Special Issue "Bacteriophages: Alternatives to Antibiotics and Beyond"

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Bacteriophages".

Deadline for manuscript submissions: closed (30 April 2019).

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A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Pilar García Suárez
Website
Guest Editor
Instituto de Productos Lácteos de Asturias (IPLA-CSIC), 33300 Villaviciosa, Asturias, Spain
Interests: bacteriophages; endolysins; phage therapy; biocontrol; Staphylococcus aureus; biofilms
Special Issues and Collections in MDPI journals
Dr. Lucía Fernández
Website
Guest Editor
CSIC - Instituto de Productos Lacteos de Asturias (IPLA), Villaviciosa, Spain
Interests: phage-derived antimicrobials; anti-biofilm strategies
Special Issues and Collections in MDPI journals

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

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Keywords

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

Published Papers (22 papers)

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Research

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Open AccessArticle
Synergistic Action of Phage and Antibiotics: Parameters to Enhance the Killing Efficacy Against Mono and Dual-Species Biofilms
Antibiotics 2019, 8(3), 103; https://doi.org/10.3390/antibiotics8030103 - 25 Jul 2019
Cited by 21
Abstract
Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens and are commonly found in polymicrobial biofilm-associated diseases, namely chronic wounds. Their co-existence in a biofilm contributes to an increased tolerance of the biofilm to antibiotics. Combined treatments of bacteriophages and antibiotics have shown a [...] Read more.
Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens and are commonly found in polymicrobial biofilm-associated diseases, namely chronic wounds. Their co-existence in a biofilm contributes to an increased tolerance of the biofilm to antibiotics. Combined treatments of bacteriophages and antibiotics have shown a promising antibiofilm activity, due to the profound differences in their mechanisms of action. In this study, 48 h old mono and dual-species biofilms were treated with a newly isolated P. aeruginosa infecting phage (EPA1) and seven different antibiotics (gentamicin, kanamycin, tetracycline, chloramphenicol, erythromycin, ciprofloxacin, and meropenem), alone and in simultaneous or sequential combinations. The therapeutic efficacy of the tested antimicrobials was determined. Phage or antibiotics alone had a modest effect in reducing biofilm bacteria. However, when applied simultaneously, a profound improvement in the killing effect was observed. Moreover, an impressive biofilm reduction (below the detection limit) was observed when gentamicin or ciprofloxacin were added sequentially after 6 h of phage treatment. The effect observed does not depend on the type of antibiotic but is influenced by its concentration. Moreover, in dual-species biofilms it was necessary to increase gentamicin concentration to obtain a similar killing effect as occurs in mono-species. Overall, combining phages with antibiotics can be synergistic in reducing the bacterial density in biofilms. However, the concentration of antibiotic and the time of antibiotic application are essential factors that need to be considered in the combined treatments. Full article
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Open AccessArticle
Characterization of a Lytic Bacteriophage as an Antimicrobial Agent for Biocontrol of Shiga Toxin-Producing Escherichia coli O145 Strains
Antibiotics 2019, 8(2), 74; https://doi.org/10.3390/antibiotics8020074 - 05 Jun 2019
Cited by 4
Abstract
Shiga toxin-producing Escherichia coli (STEC) O145 is one of the most prevalent non-O157 serogroups associated with foodborne outbreaks. Lytic phages are a potential alternative to antibiotics in combatting bacterial pathogens. In this study, we characterized a Siphoviridae phage lytic against STEC O145 strains [...] Read more.
Shiga toxin-producing Escherichia coli (STEC) O145 is one of the most prevalent non-O157 serogroups associated with foodborne outbreaks. Lytic phages are a potential alternative to antibiotics in combatting bacterial pathogens. In this study, we characterized a Siphoviridae phage lytic against STEC O145 strains as a novel antimicrobial agent. Escherichia phage vB_EcoS-Ro145clw (Ro145clw) was isolated and purified prior to physiological and genomic characterization. Then, in vitro antimicrobial activity against an outbreak strain, E. coli O145:H28, was evaluated. Ro145clw is a double-stranded DNA phage with a genome 42,031 bp in length. Of the 67 genes identified in the genome, 21 were annotated with functional proteins, none of which were stx genes. Ro145clw had a latent period of 21 min and a burst size of 192 phages per infected cell. The phage could sustain a wide range of pH (pH 3 to pH 10) and temperatures (−80 °C to −73 °C). Ro145clw was able to reduce E. coli O145:H28 in lysogeny broth by approximately 5 log at 37 °C in four hours. These findings indicate that the Ro145clw phage is a promising antimicrobial agent that can be used to control E. coli O145 in adverse pH and temperature conditions. Full article
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Open AccessArticle
Contributions of Net Charge on the PlyC Endolysin CHAP Domain
Antibiotics 2019, 8(2), 70; https://doi.org/10.3390/antibiotics8020070 - 28 May 2019
Cited by 2
Abstract
Bacteriophage endolysins, enzymes that degrade the bacterial peptidoglycan (PG), have gained an increasing interest as alternative antimicrobial agents, due to their ability to kill antibiotic resistant pathogens efficiently when applied externally as purified proteins. Typical endolysins derived from bacteriophage that infect Gram-positive hosts [...] Read more.
Bacteriophage endolysins, enzymes that degrade the bacterial peptidoglycan (PG), have gained an increasing interest as alternative antimicrobial agents, due to their ability to kill antibiotic resistant pathogens efficiently when applied externally as purified proteins. Typical endolysins derived from bacteriophage that infect Gram-positive hosts consist of an N-terminal enzymatically-active domain (EAD) that cleaves covalent bonds in the PG, and a C-terminal cell-binding domain (CBD) that recognizes specific ligands on the surface of the PG. Although CBDs are usually essential for the EADs to access the PG substrate, some EADs possess activity in the absence of CBDs, and a few even display better activity profiles or an extended host spectrum than the full-length endolysin. A current hypothesis suggests a net positive charge on the EAD enables it to reach the negatively charged bacterial surface via ionic interactions in the absence of a CBD. Here, we used the PlyC CHAP domain as a model EAD to further test the hypothesis. We mutated negatively charged surface amino acids of the CHAP domain that are not involved in structured regions to neutral or positively charged amino acids in order to increase the net charge from -3 to a range from +1 to +7. The seven mutant candidates were successfully expressed and purified as soluble proteins. Contrary to the current hypothesis, none of the mutants were more active than wild-type CHAP. Analysis of electrostatic surface potential implies that the surface charge distribution may affect the activity of a positively charged EAD. Thus, we suggest that while charge should continue to be considered for future engineering efforts, it should not be the sole focus of such engineering efforts. Full article
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Open AccessArticle
Directed Evolution of a Mycobacteriophage
Antibiotics 2019, 8(2), 46; https://doi.org/10.3390/antibiotics8020046 - 25 Apr 2019
Cited by 4
Abstract
Bacteriophages represent an alternative strategy to combat pathogenic bacteria. Currently, Mycobacterium tuberculosis infections constitute a major public health problem due to extensive antibiotic resistance in some strains. Using a non-pathogenic species of the same genus as an experimental model, Mycobacterium smegmatis, here [...] Read more.
Bacteriophages represent an alternative strategy to combat pathogenic bacteria. Currently, Mycobacterium tuberculosis infections constitute a major public health problem due to extensive antibiotic resistance in some strains. Using a non-pathogenic species of the same genus as an experimental model, Mycobacterium smegmatis, here we have set up a basic methodology for mycobacteriophage growth and we have explored directed evolution as a tool for increasing phage infectivity and lytic activity. We demonstrate mycobacteriophage adaptation to its host under different conditions. Directed evolution could be used for the development of future phage therapy applications against mycobacteria. Full article
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Open AccessArticle
Bystander Phage Therapy: Inducing Host-Associated Bacteria to Produce Antimicrobial Toxins against the Pathogen Using Phages
Antibiotics 2018, 7(4), 105; https://doi.org/10.3390/antibiotics7040105 - 04 Dec 2018
Cited by 4
Abstract
Brevibacillus laterosporus is often present in beehives, including presence in hives infected with the causative agent of American Foulbrood (AFB), Paenibacillus larvae. In this work, 12 B. laterosporus bacteriophages induced bactericidal products in their host. Results demonstrate that P. larvae is susceptible [...] Read more.
Brevibacillus laterosporus is often present in beehives, including presence in hives infected with the causative agent of American Foulbrood (AFB), Paenibacillus larvae. In this work, 12 B. laterosporus bacteriophages induced bactericidal products in their host. Results demonstrate that P. larvae is susceptible to antimicrobials induced from field isolates of the bystander, B. laterosporus. Bystander antimicrobial activity was specific against the pathogen and not other bacterial species, indicating that the production was likely due to natural competition between the two bacteria. Three B. laterosporus phages were combined in a cocktail to treat AFB. Healthy hives treated with B. laterosporus phages experienced no difference in brood generation compared to control hives over 8 weeks. Phage presence in bee larvae after treatment rose to 60.8 ± 3.6% and dropped to 0 ± 0.8% after 72 h. In infected hives the recovery rate was 75% when treated, however AFB spores were not susceptible to the antimicrobials as evidenced by recurrence of AFB. We posit that the effectiveness of this treatment is due to the production of the bactericidal products of B. laterosporus when infected with phages resulting in bystander-killing of P. larvae. Bystander phage therapy may provide a new avenue for antibacterial production and treatment of disease. Full article
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Open AccessArticle
Fighting Fire with Fire: Phage Potential for the Treatment of E. coli O157 Infection
Antibiotics 2018, 7(4), 101; https://doi.org/10.3390/antibiotics7040101 - 16 Nov 2018
Cited by 3
Abstract
Hemolytic–uremic syndrome is a life-threating disease most often associated with Shiga toxin-producing microorganisms like Escherichia coli (STEC), including E. coli O157:H7. Shiga toxin is encoded by resident prophages present within this bacterium, and both its production and release depend on the induction of [...] Read more.
Hemolytic–uremic syndrome is a life-threating disease most often associated with Shiga toxin-producing microorganisms like Escherichia coli (STEC), including E. coli O157:H7. Shiga toxin is encoded by resident prophages present within this bacterium, and both its production and release depend on the induction of Shiga toxin-encoding prophages. Consequently, treatment of STEC infections tend to be largely supportive rather than antibacterial, in part due to concerns about exacerbating such prophage induction. Here we explore STEC O157:H7 prophage induction in vitro as it pertains to phage therapy—the application of bacteriophages as antibacterial agents to treat bacterial infections—to curtail prophage induction events, while also reducing STEC O157:H7 presence. We observed that cultures treated with strictly lytic phages, despite being lysed, produce substantially fewer Shiga toxin-encoding temperate-phage virions than untreated STEC controls. We therefore suggest that phage therapy could have utility as a prophylactic treatment of individuals suspected of having been recently exposed to STEC, especially if prophage induction and by extension Shiga toxin production is not exacerbated. Full article
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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 - 16 May 2018
Cited by 12
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
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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 - 25 Apr 2018
Cited by 12
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
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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 - 08 Mar 2018
Cited by 4
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
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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 - 25 Feb 2018
Cited by 20
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
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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 - 13 Feb 2018
Cited by 21
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
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Open AccessArticle
Use of a Regression Model to Study Host-Genomic Determinants of Phage Susceptibility in MRSA
Antibiotics 2018, 7(1), 9; https://doi.org/10.3390/antibiotics7010009 - 29 Jan 2018
Cited by 3
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
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Open AccessArticle
Phage-Bacterial Dynamics with Spatial Structure: Self Organization around Phage Sinks Can Promote Increased Cell Densities
Antibiotics 2018, 7(1), 8; https://doi.org/10.3390/antibiotics7010008 - 29 Jan 2018
Cited by 14
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
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Review

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Open AccessReview
Phage Therapy with a Focus on the Human Microbiota
Antibiotics 2019, 8(3), 131; https://doi.org/10.3390/antibiotics8030131 - 27 Aug 2019
Cited by 11
Abstract
Bacteriophages are viruses that infect bacteria. After their discovery in the early 1900s, bacteriophages were a primary cure against infectious disease for almost 25 years, before being completely overshadowed by antibiotics. With the rise of antibiotic resistance, bacteriophages are being explored again for [...] Read more.
Bacteriophages are viruses that infect bacteria. After their discovery in the early 1900s, bacteriophages were a primary cure against infectious disease for almost 25 years, before being completely overshadowed by antibiotics. With the rise of antibiotic resistance, bacteriophages are being explored again for their antibacterial activity. One of the critical apprehensions regarding bacteriophage therapy, however, is the possibility of genome evolution, development of phage resistance, and subsequent perturbations to our microbiota. Through this review, we set out to explore the principles supporting the use of bacteriophages as a therapeutic agent, discuss the human gut microbiome in relation to the utilization of phage therapy, and the co-evolutionary arms race between host bacteria and phage in the context of the human microbiota. Full article
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Open AccessReview
Bacteriophages: Protagonists of a Post-Antibiotic Era
Antibiotics 2018, 7(3), 66; https://doi.org/10.3390/antibiotics7030066 - 27 Jul 2018
Cited by 36
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
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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 - 22 Mar 2018
Cited by 42Correction
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
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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 - 27 Feb 2018
Cited by 48
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
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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 - 24 Feb 2018
Cited by 30
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
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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 - 08 Nov 2017
Cited by 13
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
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Open AccessCase Report
Resolving Digital Staphylococcal Osteomyelitis Using Bacteriophage—A Case Report
Antibiotics 2018, 7(4), 87; https://doi.org/10.3390/antibiotics7040087 - 02 Oct 2018
Cited by 19
Abstract
Infections involving diabetic foot ulcers (DFU) are a major public health problem and have a substantial negative impact on patient outcomes. Osteomyelitis in an ulcerated foot substantially increases the difficulty of successful treatment. While literature suggests that osteomyelitis in selected patients can sometimes [...] Read more.
Infections involving diabetic foot ulcers (DFU) are a major public health problem and have a substantial negative impact on patient outcomes. Osteomyelitis in an ulcerated foot substantially increases the difficulty of successful treatment. While literature suggests that osteomyelitis in selected patients can sometimes be treated conservatively, with no, or minimal removal of bone, we do not yet have clear treatment guidelines and the standard treatment failure fallback remains amputation. The authors report on the successful treatment, with a long term follow up, of a 63 YO diabetic female with distal phalangeal osteomyelitis using bacteriophage, a form of treatment offering the potential for improved outcomes in this era of escalating antibiotic resistance and the increasingly recognized harms associated with antibiotic therapy. Full article
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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 - 23 Apr 2018
Cited by 29
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
Open AccessOpinion
Is Genetic Mobilization Considered When Using Bacteriophages in Antimicrobial Therapy?
Antibiotics 2017, 6(4), 32; https://doi.org/10.3390/antibiotics6040032 - 05 Dec 2017
Cited by 3
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
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