Special Issue "Advances in Bacteriophage Biology"

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

Deadline for manuscript submissions: closed (31 August 2021).

Special Issue Editor

Dr. Dann Turner
E-Mail Website
Guest Editor
Department of Applied Sciences, University of the West of England, Bristol, UK
Interests: bacteriophage research; Acinetobacter bacteriophages; bacteriophage genomics; biotechnology; taxonomy; phage-host interactions
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Special Issue Information

Dear Colleagues, 

Viruses is pleased to announce the creation of a collection of feature papers “Advances in Bacteriophage Biology.” This Issue aims to assemble a collection of articles that showcase emerging new approaches and developments that advance the current frontiers of fundamental and applied bacteriophage biology.  

We welcome the submission of manuscripts from Editorial Board Members and from scholars invited by the Editorial Board and the Editorial Office. Short proposals for the submission of Feature Papers are also welcomed. Please send proposals to the Viruses Editorial Office for evaluation ([email protected]). 

Dr. Dann Turner
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 2200 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.

Published Papers (12 papers)

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Research

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Article
In Vitro Characterization and In Vivo Efficacy Assessment in Galleria mellonella Larvae of Newly Isolated Bacteriophages against Escherichia coli K1
Viruses 2021, 13(10), 2005; https://doi.org/10.3390/v13102005 - 06 Oct 2021
Viewed by 285
Abstract
Extra-intestinal Escherichia coli express several virulence factors that increase their ability to colonize and survive in different localizations. The K1 capsular type is involved in several infections, including meningitis, urinary tract, and bloodstream infections. The aims of this work were to isolate, characterize, [...] Read more.
Extra-intestinal Escherichia coli express several virulence factors that increase their ability to colonize and survive in different localizations. The K1 capsular type is involved in several infections, including meningitis, urinary tract, and bloodstream infections. The aims of this work were to isolate, characterize, and assess the in vivo efficacy of phages targeting avian pathogenic E. coli (APEC) O18:K1, which shares many similarities with the human strains responsible for neonatal meningitis. Eleven phages were isolated against APEC O18:K1, and four of them presenting a narrow spectrum targeting E. coli K1 strains were further studied. The newly isolated phages vB_EcoS_K1-ULINTec2 were similar to the Siphoviridae family, and vB_EcoP_K1-ULINTec4, vB_EcoP_K1-ULINTec6, and vB_EcoP_K1-ULINTec7 to the Autographiviridae family. They are capsular type (K1) dependent and present several advantages characteristic of lytic phages, such as a short adsorption time and latent period. vB_EcoP_K1-ULINTec7 is able to target both K1 and K5 strains. This study shows that these phages replicate efficiently, both in vitro and in vivo in the Galleria mellonella model. Phage treatment increases the larvae survival rates, even though none of the phages were able to eliminate the bacterial load. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
The Holin-Endolysin Lysis System of the OP2-Like Phage X2 Infecting Xanthomonas oryzae pv. oryzae
Viruses 2021, 13(10), 1949; https://doi.org/10.3390/v13101949 - 28 Sep 2021
Viewed by 568
Abstract
Most endolysins of dsDNA phages are exported by a holin-dependent mechanism, while in some cases endolysins are exported via a holin-independent mechanism. However, it is still unclear whether the same endolysins can be exported by both holin-dependent and holin-independent mechanisms. This study investigated [...] Read more.
Most endolysins of dsDNA phages are exported by a holin-dependent mechanism, while in some cases endolysins are exported via a holin-independent mechanism. However, it is still unclear whether the same endolysins can be exported by both holin-dependent and holin-independent mechanisms. This study investigated the lysis system of OP2-like phage X2 infecting Xanthomonas oryzae pv. oryzae, causing devastating bacterial leaf blight disease in rice. Based on bioinformatics and protein biochemistry methods, we show that phage X2 employs the classic "holin-endolysin" lysis system. The endolysin acts on the cell envelope and exhibits antibacterial effects in vitro, while the holin facilitates the release of the protein into the periplasm. We also characterized the role of the transmembrane domain (TMD) in the translocation of the endolysin across the inner membrane. We found that the TMD facilitated the translocation of the endolysin via the Sec secretion system. The holin increases the efficiency of protein release, leading to faster and more efficient lysis. Interestingly, in E. coli, the expression of either holin or endolysin with TMDs resulted in the formation of long rod shaped cells. We conclude that the TMD of X2-Lys plays a dual role: One is the transmembrane transport while the other is the inhibition of cell division, resulting in larger cells and thus in a higher number of released viruses per cell. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
Characterization of a Novel Phage ΦAb1656-2 and Its Endolysin with Higher Antimicrobial Activity against Multidrug-Resistant Acinetobacter baumannii
Viruses 2021, 13(9), 1848; https://doi.org/10.3390/v13091848 - 16 Sep 2021
Viewed by 582
Abstract
Acinetobacter baumannii is a nosocomial pathogen, which is a problem worldwide due to the emergence of a difficult-to-treat multidrug-resistant A. baumannii (MDRAB). Endolysins are hydrolytic enzymes produced by a bacteriophage that can be used as a potential therapeutic agent for multidrug-resistant bacterial infection [...] Read more.
Acinetobacter baumannii is a nosocomial pathogen, which is a problem worldwide due to the emergence of a difficult-to-treat multidrug-resistant A. baumannii (MDRAB). Endolysins are hydrolytic enzymes produced by a bacteriophage that can be used as a potential therapeutic agent for multidrug-resistant bacterial infection in replacing antibiotics. Here, we isolated a novel bacteriophage through prophage induction using mitomycin C from clinical A. baumannii 1656-2. Morphologically, ΦAb1656-2 was identified as a Siphoviridae family bacteriophage, which can infect MDRAB. The whole genome of ΦAb1656-2 was sequenced, and it showed that it is 50.9 kb with a G + C content of 38.6% and 68 putative open reading frames (ORFs). A novel endolysin named AbEndolysin with an N-acetylmuramidase-containing catalytic domain was identified, expressed, and purified from ΦAb1656-2. Recombinant AbEndolysin showed significant antibacterial activity against MDRAB clinical strains without any outer membrane permeabilizer. These results suggest that AbEndolysin could represent a potential antimicrobial agent for treating MDRAB clinical isolates. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
Novel Acinetobacter baumannii Bacteriophage Aristophanes Encoding Structural Polysaccharide Deacetylase
Viruses 2021, 13(9), 1688; https://doi.org/10.3390/v13091688 - 26 Aug 2021
Viewed by 743
Abstract
Acinetobacter baumannii appears to be one of the most crucial nosocomial pathogens. A possible component of antimicrobial therapy for infections caused by extremely drug-resistant A. baumannii strains may be specific lytic bacteriophages or phage-derived enzymes. In the present study, we observe the biological [...] Read more.
Acinetobacter baumannii appears to be one of the most crucial nosocomial pathogens. A possible component of antimicrobial therapy for infections caused by extremely drug-resistant A. baumannii strains may be specific lytic bacteriophages or phage-derived enzymes. In the present study, we observe the biological features, genomic organization, and phage–host interaction strategy of novel virulent bacteriophage Aristophanes isolated on A. baumannii strain having K26 capsular polysaccharide structure. According to phylogenetic analysis phage Aristophanes can be classified as a representative of a new distinct genus of the subfamily Beijerinckvirinae of the family Autographiviridae. This is the first reported A. baumannii phage carrying tailspike deacetylase, which caused O-acetylation of one of the K26 sugar residues. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
RNA and Sugars, Unique Properties of Bacteriophages Infecting Multidrug Resistant Acinetobacter radioresistens Strain LH6
Viruses 2021, 13(8), 1652; https://doi.org/10.3390/v13081652 - 20 Aug 2021
Viewed by 650
Abstract
Bacteriophages (phages) are predicted to be the most ubiquitous biological entity on earth, and yet, there are still vast knowledge gaps in our understanding of phage diversity and phage–host interactions. Approximately one hundred Acinetobacter-infecting DNA viruses have been identified, and in this [...] Read more.
Bacteriophages (phages) are predicted to be the most ubiquitous biological entity on earth, and yet, there are still vast knowledge gaps in our understanding of phage diversity and phage–host interactions. Approximately one hundred Acinetobacter-infecting DNA viruses have been identified, and in this report, we describe eight more. We isolated two typical dsDNA lytic podoviruses (CAP1–2), five unique dsRNA lytic cystoviruses (CAP3–7), and one dsDNA lysogenic siphovirus (SLAP1), all capable of infecting the multidrug resistant isolate Acinetobacter radioresistens LH6. Using transmission electron microscopy, bacterial mutagenesis, phage infectivity assays, carbohydrate staining, mass-spectrometry, genomic sequencing, and comparative studies, we further characterized these phages. Mutation of the LH6 initiating glycosyltransferase homolog, PglC, necessary for both O-linked glycoprotein and capsular polysaccharide (CPS) biosynthesis, prevented infection by the lytic podovirus CAP1, while mutation of the pilin protein, PilA, prevented infection by CAP3, representing the lytic cystoviruses. Genome sequencing of the three dsRNA segments of the isolated cystoviruses revealed low levels of homology, but conserved synteny with the only other reported cystoviruses that infect Pseudomonas species. In Pseudomonas, the cystoviruses are known to be enveloped phages surrounding their capsids with the inner membrane from the infected host. To characterize any membrane-associated glycoconjugates in the CAP3 cystovirus, carbohydrate staining was used to identify a low molecular weight lipid-linked glycoconjugate subsequently identified by mutagenesis and mass-spectrometry as bacterial lipooligosaccharide. Together, this study demonstrates the isolation of new Acinetobacter-infecting phages and the determination of their cell receptors. Further, we describe the genomes of a new genus of Cystoviruses and perform an initial characterization of membrane-associated glycoconjugates. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
The Mycobacteriophage Ms6 LysB N-Terminus Displays Peptidoglycan Binding Affinity
Viruses 2021, 13(7), 1377; https://doi.org/10.3390/v13071377 - 15 Jul 2021
Viewed by 695
Abstract
Double-stranded DNA bacteriophages end their lytic cycle by disrupting the host cell envelope, which allows the release of the virion progeny. Each phage must synthesize lysis proteins that target each cell barrier to phage release. In addition to holins, which permeabilize the cytoplasmic [...] Read more.
Double-stranded DNA bacteriophages end their lytic cycle by disrupting the host cell envelope, which allows the release of the virion progeny. Each phage must synthesize lysis proteins that target each cell barrier to phage release. In addition to holins, which permeabilize the cytoplasmic membrane, and endolysins, which disrupt the peptidoglycan (PG), mycobacteriophages synthesize a specific lysis protein, LysB, capable of detaching the outer membrane from the complex cell wall of mycobacteria. The family of LysB proteins is highly diverse, with many members presenting an extended N-terminus. The N-terminal region of mycobacteriophage Ms6 LysB shows structural similarity to the PG-binding domain (PGBD) of the φKZ endolysin. A fusion of this region with enhanced green fluorescent protein (Ms6LysBPGBD-EGFP) was shown to bind to Mycobacterium smegmatis, Mycobacterium vaccae, Mycobacterium bovis BGC and Mycobacterium tuberculosis H37Ra cells pretreated with SDS or Ms6 LysB. In pulldown assays, we demonstrate that Ms6 LysB and Ms6LysBPGBD-EGFP bind to purified peptidoglycan of M. smegmatis, Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis, demonstrating affinity to PG of the A1γ chemotype. An infection assay with an Ms6 mutant producing a truncated version of LysB lacking the first 90 amino acids resulted in an abrupt lysis. These results clearly demonstrate that the N-terminus of Ms6 LysB binds to the PG. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
Emerging Phage Resistance in Pseudomonas aeruginosa PAO1 Is Accompanied by an Enhanced Heterogeneity and Reduced Virulence
Viruses 2021, 13(7), 1332; https://doi.org/10.3390/v13071332 - 10 Jul 2021
Cited by 2 | Viewed by 799
Abstract
Bacterial surface structures of a proteinic nature and glycoconjugates contribute to biofilm formation and provide shields to host defense mechanisms (e.g., the complement system and phagocytosis). A loss or alteration of these molecules, leading to phage resistance, could result in fewer virulent bacteria. [...] Read more.
Bacterial surface structures of a proteinic nature and glycoconjugates contribute to biofilm formation and provide shields to host defense mechanisms (e.g., the complement system and phagocytosis). A loss or alteration of these molecules, leading to phage resistance, could result in fewer virulent bacteria. In this study, we evaluate the biology and phenotype changes in Pseudomonas aeruginosa PAO1 phage-resistant clones, which emerge in phage-treated biofilms. We characterize these clones for phage-typing patterns, antibiotic resistance, biofilm formation, pathogenicity, and interactions with the innate immune system. Another important question that we address is whether phage-resistant mutants are also generated incidentally, despite the phage treatment-selective pressure, as the natural adaptation of the living biofilm population. It is found that the application of different phages targeting a particular receptor selects similar phage resistance patterns. Nevertheless, this results in a dramatic increase in the population heterogeneity, giving over a dozen phage-typing patterns, compared to one of the untreated PAO1 sessile forms. We also confirm the hypothesis that “phage-resistant bacteria are more susceptible to antibiotics and host-clearance mechanisms by the immune system”. These findings support phage application in therapy, although the overall statement that phage treatment selects the less virulent bacterial population should be further verified using a bigger collection of clinical strains. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
PhaLP: A Database for the Study of Phage Lytic Proteins and Their Evolution
Viruses 2021, 13(7), 1240; https://doi.org/10.3390/v13071240 - 26 Jun 2021
Viewed by 1421
Abstract
Phage lytic proteins are a clinically advanced class of novel enzyme-based antibiotics, so-called enzybiotics. A growing community of researchers develops phage lytic proteins with the perspective of their use as enzybiotics. A successful translation of enzybiotics to the market requires well-considered selections of [...] Read more.
Phage lytic proteins are a clinically advanced class of novel enzyme-based antibiotics, so-called enzybiotics. A growing community of researchers develops phage lytic proteins with the perspective of their use as enzybiotics. A successful translation of enzybiotics to the market requires well-considered selections of phage lytic proteins in early research stages. Here, we introduce PhaLP, a database of phage lytic proteins, which serves as an open portal to facilitate the development of phage lytic proteins. PhaLP is a comprehensive, easily accessible and automatically updated database (currently 16,095 entries). Capitalizing on the rich content of PhaLP, we have mapped the high diversity of natural phage lytic proteins and conducted analyses at three levels to gain insight in their host-specific evolution. First, we provide an overview of the modular diversity. Secondly, datamining and interpretable machine learning approaches were adopted to reveal host-specific design rules for domain architectures in endolysins. Lastly, the evolution of phage lytic proteins on the protein sequence level was explored, revealing host-specific clusters. In sum, PhaLP can act as a starting point for the broad community of enzybiotic researchers, while the steadily improving evolutionary insights will serve as a natural inspiration for protein engineers. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
Gold—Polyoxoborates Nanocomposite Prohibits Adsorption of Bacteriophages on Inner Surfaces of Polypropylene Labware and Protects Samples from Bacterial and Yeast Infections
Viruses 2021, 13(7), 1206; https://doi.org/10.3390/v13071206 - 23 Jun 2021
Viewed by 732
Abstract
Bacteriophages (phages) are a specific type of viruses that infect bacteria. Because of growing antibiotic resistance among bacterial strains, phage-based therapies are becoming more and more attractive. The critical problem is the storage of bacteriophages. Recently, it was found that bacteriophages might adsorb [...] Read more.
Bacteriophages (phages) are a specific type of viruses that infect bacteria. Because of growing antibiotic resistance among bacterial strains, phage-based therapies are becoming more and more attractive. The critical problem is the storage of bacteriophages. Recently, it was found that bacteriophages might adsorb on the surfaces of plastic containers, effectively decreasing the titer of phage suspensions. Here, we showed that a BOA nanocomposite (gold nanoparticles embedded in polyoxoborate matrix) deposited onto the inner walls of the containers stabilizes phage suspensions against uncontrolled adsorption and titer decrease. Additionally, BOA provides antibacterial and antifungal protection. The application of BOA assures safe and sterile means for the storage of bacteriophages. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Article
Isolation and Characterization of Streptococcus mutans Phage as a Possible Treatment Agent for Caries
Viruses 2021, 13(5), 825; https://doi.org/10.3390/v13050825 - 02 May 2021
Cited by 2 | Viewed by 899
Abstract
Streptococcus mutans is a key bacterium in dental caries, one of the most prevalent chronic infectious diseases. Conventional treatment fails to specifically target the pathogenic bacteria, while tending to eradicate commensal bacteria. Thus, caries remains one of the most common and challenging diseases. [...] Read more.
Streptococcus mutans is a key bacterium in dental caries, one of the most prevalent chronic infectious diseases. Conventional treatment fails to specifically target the pathogenic bacteria, while tending to eradicate commensal bacteria. Thus, caries remains one of the most common and challenging diseases. Phage therapy, which involves the use of bacterial viruses as anti-bacterial agents, has been gaining interest worldwide. Nevertheless, to date, only a few phages have been isolated against S. mutans. In this study, we describe the isolation and characterization of a new S. mutans phage, termed SMHBZ8, from hundreds of human saliva samples that were collected, filtered, and screened. The SMHBZ8 genome was sequenced and analyzed, visualized by TEM, and its antibacterial properties were evaluated in various states. In addition, we tested the lytic efficacy of SMHBZ8 against S. mutans in a human cariogenic dentin model. The isolation and characterization of SMHBZ8 may be the first step towards developing a potential phage therapy for dental caries. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Review

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Review
Advances in Phage Therapy: Targeting the Burkholderia cepacia Complex
Viruses 2021, 13(7), 1331; https://doi.org/10.3390/v13071331 - 09 Jul 2021
Viewed by 766
Abstract
The increasing prevalence and worldwide distribution of multidrug-resistant bacterial pathogens is an imminent danger to public health and threatens virtually all aspects of modern medicine. Particularly concerning, yet insufficiently addressed, are the members of the Burkholderia cepacia complex (Bcc), a group of at [...] Read more.
The increasing prevalence and worldwide distribution of multidrug-resistant bacterial pathogens is an imminent danger to public health and threatens virtually all aspects of modern medicine. Particularly concerning, yet insufficiently addressed, are the members of the Burkholderia cepacia complex (Bcc), a group of at least twenty opportunistic, hospital-transmitted, and notoriously drug-resistant species, which infect and cause morbidity in patients who are immunocompromised and those afflicted with chronic illnesses, including cystic fibrosis (CF) and chronic granulomatous disease (CGD). One potential solution to the antimicrobial resistance crisis is phage therapy—the use of phages for the treatment of bacterial infections. Although phage therapy has a long and somewhat checkered history, an impressive volume of modern research has been amassed in the past decades to show that when applied through specific, scientifically supported treatment strategies, phage therapy is highly efficacious and is a promising avenue against drug-resistant and difficult-to-treat pathogens, such as the Bcc. In this review, we discuss the clinical significance of the Bcc, the advantages of phage therapy, and the theoretical and clinical advancements made in phage therapy in general over the past decades, and apply these concepts specifically to the nascent, but growing and rapidly developing, field of Bcc phage therapy. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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Review
Temperate Bacteriophages—The Powerful Indirect Modulators of Eukaryotic Cells and Immune Functions
Viruses 2021, 13(6), 1013; https://doi.org/10.3390/v13061013 - 28 May 2021
Cited by 1 | Viewed by 1165
Abstract
Bacteriophages are natural biological entities that limit the growth and amplification of bacteria. They are important stimulators of evolutionary variability in bacteria, and currently are considered a weapon against antibiotic resistance of bacteria. Nevertheless, apart from their antibacterial activity, phages may act as [...] Read more.
Bacteriophages are natural biological entities that limit the growth and amplification of bacteria. They are important stimulators of evolutionary variability in bacteria, and currently are considered a weapon against antibiotic resistance of bacteria. Nevertheless, apart from their antibacterial activity, phages may act as modulators of mammalian immune responses. In this paper, we focus on temperate phages able to execute the lysogenic development, which may shape animal or human immune response by influencing various processes, including phagocytosis of bacterial invaders and immune modulation of mammalian host cells. Full article
(This article belongs to the Special Issue Advances in Bacteriophage Biology)
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