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Bacteriophage—Molecular Studies 4.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (20 October 2022) | Viewed by 38805

Special Issue Editor


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Guest Editor
Phage Therapy Center, University Center for Applied and Interdisciplinary Research, University of Gdansk, Gdansk, Poland
Interests: biology of bacteriophages; biodiversity of bacteriophages; regulation of bacteriophage development; regulation of phage gene expression; control of phage DNA replication; phage therapy; phages bearing genes of toxins; bacteriophage genomics
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Special Issue Information

Dear Colleagues,

Bacteriophages, the viruses infecting bacterial cells, were first described 100 years ago, in 1915, by Frederick Twort. The scientist who introduced the name “bacteriophage” was Felix d’Herelle, who investigated these viruses for many years, leading to new fields of research, including bacteriophage therapy. In the following years, bacteriophages became important model organisms in molecular biology and genetics. Many basic discoveries were made during studies of these viruses, with such spectacular examples as demonstrating that DNA is a genetic material, viruses can encode enzymes, gene expression proceeds through mRNA molecules, the genetic code is based on nucleotide triplets, gene expression can be regulated by transcription antitermination, specific genes encode heat shock proteins, and specific mechanisms regulate DNA replication initiation based on the formation and rearrangements of protein–DNA complexes. The regulatory processes occurring in bacteriophage-infected cells have been considered paradigms of the control of developmental pathways. On the other hand, the history of research on bacteriophages also passed through dark times when, at the end of 20th century, there was the collective impression that we knew almost everything there was to know about these simple viruses, and that it was time to investigate more complex organisms instead. Nevertheless, subsequent discoveries have indicated that such an assumption was unequivocally false, and studies on the molecular biology and biotechnology of bacteriophages have once again become extensive. The interest in these viruses has increased dramatically, and it appears that we are far from understanding the biology of the vast majority of bacteriophages.

This Special Issue of the International Journal of Molecular Sciences is devoted to publishing papers on studies of bacteriophages at the molecular level. Papers on phage biodiversity, regulation of processes occurring during phage development, as well as the practical use of bacteriophages—including biotechnology and phage therapy—are welcome, providing the studies deal with the molecular level and utilize molecular biology methods. I am hopeful of building a great collection of articles devoted to recent discoveries in the field of bacteriophage molecular biology. Therefore, I invite you to submit manuscripts to this Special Issue as an excellent forum to share your discoveries in this fascinating research field.

Dr. Alicja Wegrzyn
Guest Editor

Manuscript Submission Information

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Keywords

  • bacteriophage biodiversity
  • regulation of bacteriophage development
  • molecular processes in bacteriophages
  • bacteriophage-based biotechnology
  • phage therapy

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Published Papers (12 papers)

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17 pages, 3180 KiB  
Article
Comprehensive Characterization of a Novel Bacteriophage, vB_VhaS_MAG7 against a Fish Pathogenic Strain of Vibrio harveyi and Its In Vivo Efficacy in Phage Therapy Trials
by Stavros Droubogiannis, Lydia Pavlidi, Dimitrios Skliros, Emmanouil Flemetakis and Pantelis Katharios
Int. J. Mol. Sci. 2023, 24(9), 8200; https://doi.org/10.3390/ijms24098200 - 3 May 2023
Cited by 4 | Viewed by 2355
Abstract
Vibrio harveyi, a significant opportunistic marine pathogen, has been a challenge to the aquaculture industry, leading to severe economical and production losses. Phage therapy has been an auspicious approach in controlling such bacterial infections in the era of antimicrobial resistance. In this [...] Read more.
Vibrio harveyi, a significant opportunistic marine pathogen, has been a challenge to the aquaculture industry, leading to severe economical and production losses. Phage therapy has been an auspicious approach in controlling such bacterial infections in the era of antimicrobial resistance. In this study, we isolated and fully characterized a novel strain-specific phage, vB_VhaS_MAG7, which infects V. harveyi MM46, and tested its efficacy as a therapeutic agent in challenged gilthead seabream larvae. vB_VhaS_MAG7 is a tailed bacteriophage with a double-stranded DNA of 49,315 bp. No genes linked with virulence or antibiotic resistance were harbored in the genome. The phage had a remarkably large burst size of 1393 PFU cell−1 and showed strong lytic ability in in vitro assays. When applied in phage therapy trials in challenged gilthead seabream larvae, vB_VhaS_MAG7 was capable of improving the survival of the larvae up to 20%. Due to its distinct features and safety, vB_VhaS_MAG7 is considered a suitable candidate for applied phage therapy. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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20 pages, 1931 KiB  
Article
Characteristics and Comparative Genomic Analysis of a Novel Virus, VarioGold, the First Bacteriophage of Variovorax
by Przemyslaw Decewicz, Michal Kitowicz and Monika Radlinska
Int. J. Mol. Sci. 2022, 23(21), 13539; https://doi.org/10.3390/ijms232113539 - 4 Nov 2022
Cited by 2 | Viewed by 2510
Abstract
Variovorax represents a widespread and ecologically significant genus of soil bacteria. Despite the ecological importance of these bacteria, our knowledge about the viruses infecting Variovorax spp. is quite poor. This study describes the isolation and characterization of the mitomycin-induced phage, named VarioGold. To [...] Read more.
Variovorax represents a widespread and ecologically significant genus of soil bacteria. Despite the ecological importance of these bacteria, our knowledge about the viruses infecting Variovorax spp. is quite poor. This study describes the isolation and characterization of the mitomycin-induced phage, named VarioGold. To the best of our knowledge, VarioGold represents the first characterized virus for this genus. Comparative genomic analyses suggested that VarioGold is distinct from currently known bacteriophages at both the nucleotide and protein levels; thus, it could be considered a new virus genus. In addition, another 37 prophages were distinguished in silico within the complete genomic sequences of Variovorax spp. that are available in public databases. The similarity networking analysis highlighted their general high diversity, which, despite clustering with previously described phages, shows their unique genetic load. Therefore, the novelty of Variovorax phages warrants the great enrichment of databases, which could, in turn, improve bioinformatic strategies for finding (pro)phages. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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12 pages, 14902 KiB  
Article
A Combination of Virulent and Non-Productive Phages Synergizes the Immune System against Salmonella Typhimurium Systemic Infection
by Lu Liang, Jiaqi Huang, Ketong Cui, Peiyong Li, Wenjian Shi, Fang Lin, Guijuan Hao and Shuhong Sun
Int. J. Mol. Sci. 2022, 23(21), 12830; https://doi.org/10.3390/ijms232112830 - 24 Oct 2022
Cited by 4 | Viewed by 1880
Abstract
Effective phage cocktails consisting of multiple virus types are essential for successful phage therapy against pandrug-resistant pathogens, including Salmonella enterica serovar (S.) Typhimurium. Here we show that a Salmonella phage, F118P13, with non-productive infection and a lytic phage, PLL1, combined to [...] Read more.
Effective phage cocktails consisting of multiple virus types are essential for successful phage therapy against pandrug-resistant pathogens, including Salmonella enterica serovar (S.) Typhimurium. Here we show that a Salmonella phage, F118P13, with non-productive infection and a lytic phage, PLL1, combined to inhibit pandrug-resistant S. Typhimurium growth and significantly limited resistance to phages in vitro. Further, intraperitoneal injection with this unique phage combination completely protected mice from Salmonella-induced death and inhibited bacterial proliferation rapidly in various organs. Furthermore, the phage combination treatment significantly attenuated the inflammatory response, restored the generation of CD4+ T cells repressed by Salmonella, and allowed macrophages and granulocytes to participate in immunophage synergy to promote bacterial clearance. Crucially, the non-productive phage F118P13 is less likely to be cleared by the immune system in vivo, thus providing an alternative to phage cocktail against bacterial infections. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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17 pages, 3517 KiB  
Article
RB49-like Bacteriophages Recognize O Antigens as One of the Alternative Primary Receptors
by Alexandr D. Efimov, Alla K. Golomidova, Eugene E. Kulikov, Ilya S. Belalov, Pavel A. Ivanov and Andrey V. Letarov
Int. J. Mol. Sci. 2022, 23(19), 11329; https://doi.org/10.3390/ijms231911329 - 26 Sep 2022
Cited by 4 | Viewed by 2137
Abstract
The power of most of the enterobacterial O antigen types to provide robust protection against direct recognition of the cell surface by bacteriophage receptor-recognition proteins (RBP) has been recently recognized. The bacteriophages infecting O antigen producing strains of E. coli employ various strategies [...] Read more.
The power of most of the enterobacterial O antigen types to provide robust protection against direct recognition of the cell surface by bacteriophage receptor-recognition proteins (RBP) has been recently recognized. The bacteriophages infecting O antigen producing strains of E. coli employ various strategies to tackle this nonspecific protection. T-even related phages, including RB49-like viruses, often have wide host ranges, being considered good candidates for use in phage therapy. However, the mechanisms by which these phages overcome the O antigen barrier remain unknown. We demonstrate here that RB49 and related phages Cognac49 and Whisky49 directly use certain types of O antigen as their primary receptors recognized by the virus long tail fibers (LTF) RBP gp38, so the O antigen becomes an attractant instead of an obstacle. Simultaneously to recognize multiple O antigen types, LTFs of each of these phages can bind to additional receptors, such as OmpA protein, enabling them to infect some rough strains of E. coli. We speculate that the mechanical force of the deployment of the short tail fibers (STF) triggered by the LTF binding to the O antigen or underneath of it, allows the receptor binding domains of STF to break through the O polysaccharide layer. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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18 pages, 3660 KiB  
Article
Pectobacterium versatile Bacteriophage Possum: A Complex Polysaccharide-Deacetylating Tail Fiber as a Tool for Host Recognition in Pectobacterial Schitoviridae
by Anna A. Lukianova, Peter V. Evseev, Mikhail M. Shneider, Elena A. Dvoryakova, Anna D. Tokmakova, Anna M. Shpirt, Marsel R. Kabilov, Ekaterina A. Obraztsova, Alexander S. Shashkov, Alexander N. Ignatov, Yuriy A. Knirel, Fevzi S.-U. Dzhalilov and Konstantin A. Miroshnikov
Int. J. Mol. Sci. 2022, 23(19), 11043; https://doi.org/10.3390/ijms231911043 - 20 Sep 2022
Cited by 5 | Viewed by 2329
Abstract
Novel, closely related phages Possum and Horatius infect Pectobacterium versatile, a phytopathogen causing soft rot in potatoes and other essential plants. Their properties and genomic composition define them as N4-like bacteriophages of the genus Cbunavirus, a part of a recently formed [...] Read more.
Novel, closely related phages Possum and Horatius infect Pectobacterium versatile, a phytopathogen causing soft rot in potatoes and other essential plants. Their properties and genomic composition define them as N4-like bacteriophages of the genus Cbunavirus, a part of a recently formed family Schitoviridae. It is proposed that the adsorption apparatus of these phages consists of tail fibers connected to the virion through an adapter protein. Tail fibers possess an enzymatic domain. Phage Possum uses it to deacetylate O-polysaccharide on the surface of the host strain to provide viral attachment. Such an infection mechanism is supposed to be common for all Cbunavirus phages and this feature should be considered when designing cocktails for phage control of soft rot. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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18 pages, 2806 KiB  
Article
Interaction between Phage T4 Protein RIII and Host Ribosomal Protein S1 Inhibits Endoribonuclease RegB Activation
by Augustinas Juškauskas, Aurelija Zajančkauskaitė, Rolandas Meškys, Marija Ger, Algirdas Kaupinis, Mindaugas Valius and Lidija Truncaitė
Int. J. Mol. Sci. 2022, 23(16), 9483; https://doi.org/10.3390/ijms23169483 - 22 Aug 2022
Cited by 3 | Viewed by 2218
Abstract
Lytic viruses of bacteria (bacteriophages, phages) are intracellular parasites that take over hosts’ biosynthetic processes for their propagation. Most of the knowledge on the host hijacking mechanisms has come from the studies of the lytic phage T4, which infects Escherichia coli. The [...] Read more.
Lytic viruses of bacteria (bacteriophages, phages) are intracellular parasites that take over hosts’ biosynthetic processes for their propagation. Most of the knowledge on the host hijacking mechanisms has come from the studies of the lytic phage T4, which infects Escherichia coli. The integrity of T4 development is achieved by strict control over the host and phage processes and by adjusting them to the changing infection conditions. In this study, using in vitro and in vivo biochemical methods, we detected the direct interaction between the T4 protein RIII and ribosomal protein S1 of the host. Protein RIII is known as a cytoplasmic antiholin, which plays a role in the lysis inhibition function of T4. However, our results show that RIII also acts as a viral effector protein mainly targeting S1 RNA-binding domains that are central for all the activities of this multifunctional protein. We confirm that the S1–RIII interaction prevents the S1-dependent activation of endoribonuclease RegB. In addition, we propose that by modulating the multiple processes mediated by S1, RIII could act as a regulator of all stages of T4 infection including the lysis inhibition state. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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16 pages, 1749 KiB  
Article
Standing Genetic Diversity and Transmission Bottleneck Size Drive Adaptation in Bacteriophage Qβ
by Pilar Somovilla, Alicia Rodríguez-Moreno, María Arribas, Susanna Manrubia and Ester Lázaro
Int. J. Mol. Sci. 2022, 23(16), 8876; https://doi.org/10.3390/ijms23168876 - 9 Aug 2022
Cited by 6 | Viewed by 2322
Abstract
A critical issue to understanding how populations adapt to new selective pressures is the relative contribution of the initial standing genetic diversity versus that generated de novo. RNA viruses are an excellent model to study this question, as they form highly heterogeneous populations [...] Read more.
A critical issue to understanding how populations adapt to new selective pressures is the relative contribution of the initial standing genetic diversity versus that generated de novo. RNA viruses are an excellent model to study this question, as they form highly heterogeneous populations whose genetic diversity can be modulated by factors such as the number of generations, the size of population bottlenecks, or exposure to new environment conditions. In this work, we propagated at nonoptimal temperature (43 °C) two bacteriophage Qβ populations differing in their degree of heterogeneity. Deep sequencing analysis showed that, prior to the temperature change, the most heterogeneous population contained some low-frequency mutations that had previously been detected in the consensus sequences of other Qβ populations adapted to 43 °C. Evolved populations with origin in this ancestor reached similar growth rates, but the adaptive pathways depended on the frequency of these standing mutations and the transmission bottleneck size. In contrast, the growth rate achieved by populations with origin in the less heterogeneous ancestor did depend on the transmission bottleneck size. The conclusion is that viral diversification in a particular environment may lead to the emergence of mutants capable of accelerating adaptation when the environment changes. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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14 pages, 4454 KiB  
Article
Specific Isolation of Clostridium botulinum Group I Cells by Phage Lysin Cell Wall Binding Domain with the Aid of S-Layer Disruption
by Zhen Zhang, François P. Douillard, Hannu Korkeala and Miia Lindström
Int. J. Mol. Sci. 2022, 23(15), 8391; https://doi.org/10.3390/ijms23158391 - 29 Jul 2022
Cited by 2 | Viewed by 3593
Abstract
Clostridium botulinum is a notorious pathogen that raises health and food safety concerns by producing the potent botulinum neurotoxin and causing botulism, a potentially fatal neuroparalytic disease in humans and animals. Efficient methods for the identification and isolation of C. botulinum are warranted [...] Read more.
Clostridium botulinum is a notorious pathogen that raises health and food safety concerns by producing the potent botulinum neurotoxin and causing botulism, a potentially fatal neuroparalytic disease in humans and animals. Efficient methods for the identification and isolation of C. botulinum are warranted for laboratory diagnostics of botulism and for food safety risk assessment. The cell wall binding domains (CBD) of phage lysins are recognized by their high specificity and affinity to distinct types of bacteria, which makes them promising for the development of diagnostic tools. We previously identified CBO1751, which is the first antibotulinal phage lysin showing a lytic activity against C. botulinum Group I. In this work, we assessed the host specificity of the CBD of CBO1751 and tested its feasibility as a probe for the specific isolation of C. botulinum Group I strains. We show that the CBO1751 CBD specifically binds to C. botulinum Group I sensu lato (including C. sporogenes) strains. We also demonstrate that some C. botulinum Group I strains possess an S-layer, the disruption of which by an acid glycine treatment is required for efficient binding of the CBO1751 CBD to the cells of these strains. We further developed CBO1751 CBD-based methods using flow cytometry and magnetic separation to specifically isolate viable cells of C. botulinum Group I. These methods present potential for applications in diagnostics and risk assessment in order to control the botulism hazard. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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19 pages, 2534 KiB  
Article
Cloning and Characterization of a Thermostable Endolysin of Bacteriophage TP-84 as a Potential Disinfectant and Biofilm-Removing Biological Agent
by Joanna Żebrowska, Olga Żołnierkiewicz, Małgorzata Ponikowska, Michał Puchalski, Natalia Krawczun, Joanna Makowska and Piotr Skowron
Int. J. Mol. Sci. 2022, 23(14), 7612; https://doi.org/10.3390/ijms23147612 - 9 Jul 2022
Cited by 11 | Viewed by 2520
Abstract
The obligatory step in the life cycle of a lytic bacteriophage is the release of its progeny particles from infected bacterial cells. The main barrier to overcome is the cell wall, composed of crosslinked peptidoglycan, which counteracts the pressure prevailing in the cytoplasm [...] Read more.
The obligatory step in the life cycle of a lytic bacteriophage is the release of its progeny particles from infected bacterial cells. The main barrier to overcome is the cell wall, composed of crosslinked peptidoglycan, which counteracts the pressure prevailing in the cytoplasm and protects the cell against osmotic lysis and mechanical damage. Bacteriophages have developed two strategies leading to the release of progeny particles: the inhibition of peptidoglycan synthesis and enzymatic cleavage by a bacteriophage-coded endolysin. In this study, we cloned and investigated the TP84_28 endolysin of the bacteriophage TP-84, which infects thermophilic Geobacillus stearothermophilus, determined the enzymatic characteristics, and initially evaluated the endolysin application as a non-invasive agent for disinfecting surfaces, including those exposed to high temperatures. Both the native and recombinant TP84_28 endolysins, obtained through the Escherichia coli T7-lac expression system, are highly thermostable and retain trace activity after incubation at 100 °C for 30 min. The proteins exhibit strong bacterial wall digestion activity up to 77.6 °C, decreasing to marginal activity at ambient temperatures. We assayed the lysis of various types of bacteria using TP84_28 endolysins: Gram-positive, Gram-negative, encapsulated, and pathogenic. Significant lytic activity was observed on the thermophilic and mesophilic Gram-positive bacteria and, to a lesser extent, on the thermophilic and mesophilic Gram-negative bacteria. The thermostable TP84_28 endolysin seems to be a promising mild agent for disinfecting surfaces exposed to high temperatures. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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14 pages, 3125 KiB  
Article
Host Range, Morphology and Sequence Analysis of Ten Temperate Phages Isolated from Pathogenic Yersinia enterocolitica Strains
by Jens Andre Hammerl, Sabrin El-Mustapha, Michelle Bölcke, Hannah Trampert, Andrea Barac, Claudia Jäckel, Ashish K. Gadicherla and Stefan Hertwig
Int. J. Mol. Sci. 2022, 23(12), 6779; https://doi.org/10.3390/ijms23126779 - 17 Jun 2022
Cited by 5 | Viewed by 2124
Abstract
Yersinia enterocolitica is a heterogeneous species comprising highly pathogenic, weakly pathogenic and non-pathogenic strains. Previous data suggest that gene exchange may occur in Yersinia. Only scarce information exists about temperate phages of Y. enterocolitica, even though many prophage sequences are present in [...] Read more.
Yersinia enterocolitica is a heterogeneous species comprising highly pathogenic, weakly pathogenic and non-pathogenic strains. Previous data suggest that gene exchange may occur in Yersinia. Only scarce information exists about temperate phages of Y. enterocolitica, even though many prophage sequences are present in this species. We have examined 102 pathogenic Y. enterocolitica strains for the presence of inducible prophages by mitomycin C treatment. Ten phages were isolated from nine strains belonging to the bio (B)/serotypes (O) B2/O:5,27, B2/O:9 and 1B/O:8. All phages are myoviruses showing lytic activity only at room temperature. Whole-genome sequencing of the phage genomes revealed that they belong to three groups, which, however, are not closely related to known phages. Group 1 is composed of five phages (type phage: vB_YenM_06.16.1) with genome sizes of 43.8 to 44.9 kb, whereas the four group 2 phages (type phage: vB_YenM_06.16.2) possess smaller genomes of 29.5 to 33.2 kb. Group 3 contains only one phage (vB_YenM_42.18) whose genome has a size of 36.5 kb, which is moderately similar to group 2. The host range of the phages differed significantly. While group 1 phages almost exclusively lysed strains of B2/O:5,27, phages of group 2 and 3 were additionally able to lyse B4/O:3, and some of them even B2/O:9 and 1B/O:8 strains. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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Review

Jump to: Research

28 pages, 1127 KiB  
Review
Phage Therapy for Crops: Concepts, Experimental and Bioinformatics Approaches to Direct Its Application
by José Luis Villalpando-Aguilar, Gilberto Matos-Pech, Itzel López-Rosas, Hugo Gildardo Castelán-Sánchez and Fulgencio Alatorre-Cobos
Int. J. Mol. Sci. 2023, 24(1), 325; https://doi.org/10.3390/ijms24010325 - 25 Dec 2022
Cited by 17 | Viewed by 5339
Abstract
Phage therapy consists of applying bacteriophages, whose natural function is to kill specific bacteria. Bacteriophages are safe, evolve together with their host, and are environmentally friendly. At present, the indiscriminate use of antibiotics and salt minerals (Zn2+ or Cu2+) has [...] Read more.
Phage therapy consists of applying bacteriophages, whose natural function is to kill specific bacteria. Bacteriophages are safe, evolve together with their host, and are environmentally friendly. At present, the indiscriminate use of antibiotics and salt minerals (Zn2+ or Cu2+) has caused the emergence of resistant strains that infect crops, causing difficulties and loss of food production. Phage therapy is an alternative that has shown positive results and can improve the treatments available for agriculture. However, the success of phage therapy depends on finding effective bacteriophages. This review focused on describing the potential, up to now, of applying phage therapy as an alternative treatment against bacterial diseases, with sustainable improvement in food production. We described the current isolation techniques, characterization, detection, and selection of lytic phages, highlighting the importance of complementary studies using genome analysis of the phage and its host. Finally, among these studies, we concentrated on the most relevant bacteriophages used for biocontrol of Pseudomonas spp., Xanthomonas spp., Pectobacterium spp., Ralstonia spp., Burkholderia spp., Dickeya spp., Clavibacter michiganensis, and Agrobacterium tumefaciens as agents that cause damage to crops, and affect food production around the world. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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19 pages, 4749 KiB  
Review
Understanding Bacteriophage Tail Fiber Interaction with Host Surface Receptor: The Key “Blueprint” for Reprogramming Phage Host Range
by Jarin Taslem Mourosi, Ayobami Awe, Wenzheng Guo, Himanshu Batra, Harrish Ganesh, Xiaorong Wu and Jingen Zhu
Int. J. Mol. Sci. 2022, 23(20), 12146; https://doi.org/10.3390/ijms232012146 - 12 Oct 2022
Cited by 54 | Viewed by 7951
Abstract
Bacteriophages (phages), as natural antibacterial agents, are being rediscovered because of the growing threat of multi- and pan-drug-resistant bacterial pathogens globally. However, with an estimated 1031 phages on the planet, finding the right phage to recognize a specific bacterial host is like [...] Read more.
Bacteriophages (phages), as natural antibacterial agents, are being rediscovered because of the growing threat of multi- and pan-drug-resistant bacterial pathogens globally. However, with an estimated 1031 phages on the planet, finding the right phage to recognize a specific bacterial host is like looking for a needle in a trillion haystacks. The host range of a phage is primarily determined by phage tail fibers (or spikes), which initially mediate reversible and specific recognition and adsorption by susceptible bacteria. Recent significant advances at single-molecule and atomic levels have begun to unravel the structural organization of tail fibers and underlying mechanisms of phage–host interactions. Here, we discuss the molecular mechanisms and models of the tail fibers of the well-characterized T4 phage’s interaction with host surface receptors. Structure–function knowledge of tail fibers will pave the way for reprogramming phage host range and will bring future benefits through more-effective phage therapy in medicine. Furthermore, the design strategies of tail fiber engineering are briefly summarized, including machine-learning-assisted engineering inspired by the increasingly enormous amount of phage genetic information. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies 4.0)
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