Bacteriophages and Their Enzymes as Antibacterial Agents

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 16827

Special Issue Editors


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Guest Editor
Department of Microbiology, The Ohio State University, Columbus, OH 44906, USA
Interests: phage ecology; phage evolutionary ecology; phage therapy; phage therapy pharmacology; phage history
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA
Interests: phage therapy; phage-derived enzymes; co-treatments; biofilms

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Guest Editor
P3 Research Laboratory, Division of Outcomes and Translational Sciences, The Ohio State University, Columbus, OH, USA
Interests: antibiotic resistance; bacteriophage; lysin; pharmacokinetic/pharmacodynamic models
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, Australia
Interests: phage therapy; phage biology; L-forms; AMR

Special Issue Information

Dear Colleagues,

Bacteriophages are viruses that are able to lyse and kill bacteria. Phage therapy, or more broadly, phage-mediated biocontrol, is the use of phages or their molecular parts as antibacterial agents.  Due to the current antibiotic resistance crisis and increasing problems with the treatment of bacterial infections, there is growing interest in phage use as an antibacterial agent. Here, we welcome outstanding articles emphasizing phage therapy as well as the use of phage-derived enzymes as antibacterial agents along with related issues.

Related issues can include but are not limited to: phage delivery, phage therapy pharmacokinetics and pharmacodynamics (PK/PD), phage immunology, phage cocktail development, phage engineering, the noted phage-mediated biological control (of bacterial pathogens or other nuisance bacteria), phage–biofilm interactions, development of phage-based enzybiotics, phage co-treatments and interactions with other antibacterial agents such as antibiotics, aspects of phage–phage and phage–bacterium interactions that are important for therapeutic success, and in vitro, ex vivo, in silico, and in vivo models of phage therapy.

Prof. Dr. Stephen T. Abedon
Dr. Katarzyna Danis-Wlodarczyk
Dr. Razi Kebriaei
Dr. Aleksandra Petrovic Fabijan
Guest Editors

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Keywords

  • antibacterial therapy
  • antibiotic resistance
  • bacteriophage therapy
  • combination treatments
  • phage resistance

Published Papers (9 papers)

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Research

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22 pages, 2926 KiB  
Article
Controlling Recombination to Evolve Bacteriophages
by James J. Bull, Holly A. Wichman, Stephen M. Krone and Ian J. Molineux
Cells 2024, 13(7), 585; https://doi.org/10.3390/cells13070585 - 28 Mar 2024
Viewed by 898
Abstract
Recombination among different phages sometimes facilitates their ability to grow on new hosts. Protocols to direct the evolution of phage host range, as might be used in the application of phage therapy, would then benefit from including steps to enable recombination. Applying mathematical [...] Read more.
Recombination among different phages sometimes facilitates their ability to grow on new hosts. Protocols to direct the evolution of phage host range, as might be used in the application of phage therapy, would then benefit from including steps to enable recombination. Applying mathematical and computational models, in addition to experiments using phages T3 and T7, we consider ways that a protocol may influence recombination levels. We first address coinfection, which is the first step to enabling recombination. The multiplicity of infection (MOI, the ratio of phage to cell concentration) is insufficient for predicting (co)infection levels. The force of infection (the rate at which cells are infected) is also critical but is more challenging to measure. Using both a high force of infection and high MOI (>1) for the different phages ensures high levels of coinfection. We also apply a four-genetic-locus model to study protocol effects on recombinant levels. Recombinants accumulate over multiple generations of phage growth, less so if one phage outgrows the other. Supplementing the phage pool with the low-fitness phage recovers some of this ‘lost’ recombination. Overall, fine tuning of phage recombination rates will not be practical with wild phages, but qualitative enhancement can be attained with some basic procedures. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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13 pages, 2415 KiB  
Article
Harnessing the Diversity of Burkholderia spp. Prophages for Therapeutic Potential
by Hayley R. Nordstrom, Marissa P. Griffith, Vatsala Rangachar Srinivasa, Nathan R. Wallace, Anna Li, Vaughn S. Cooper, Ryan K. Shields and Daria Van Tyne
Cells 2024, 13(5), 428; https://doi.org/10.3390/cells13050428 - 29 Feb 2024
Viewed by 795
Abstract
Burkholderia spp. are often resistant to antibiotics, and infections with these organisms are difficult to treat. A potential alternative treatment for Burkholderia spp. infections is bacteriophage (phage) therapy; however, it can be difficult to locate phages that target these bacteria. Prophages incorporated into [...] Read more.
Burkholderia spp. are often resistant to antibiotics, and infections with these organisms are difficult to treat. A potential alternative treatment for Burkholderia spp. infections is bacteriophage (phage) therapy; however, it can be difficult to locate phages that target these bacteria. Prophages incorporated into the bacterial genome have been identified within Burkholderia spp. and may represent a source of useful phages for therapy. Here, we investigate whether prophages within Burkholderia spp. clinical isolates can kill conspecific and heterospecific isolates. Thirty-two Burkholderia spp. isolates were induced for prophage release, and harvested phages were tested for lytic activity against the same 32 isolates. Temperate phages were passaged and their host ranges were determined, resulting in four unique phages of prophage origin that showed different ranges of lytic activity. We also analyzed the prophage content of 35 Burkholderia spp. clinical isolate genomes and identified several prophages present in the genomes of multiple isolates of the same species. Finally, we observed that Burkholdera cenocepacia isolates were more phage-susceptible than Burkholderia multivorans isolates. Overall, our findings suggest that prophages present within Burkholderia spp. genomes are a potentially useful starting point for the isolation and development of novel phages for use in phage therapy. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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15 pages, 2355 KiB  
Article
Engineering of Salmonella Phages into Novel Antimicrobial Tailocins
by Cedric Woudstra, Anders Nørgaard Sørensen and Lone Brøndsted
Cells 2023, 12(22), 2637; https://doi.org/10.3390/cells12222637 - 16 Nov 2023
Cited by 1 | Viewed by 976
Abstract
Due to the extensive use of antibiotics, the increase of infections caused by antibiotic-resistant bacteria is now a global health concern. Phages have proven useful for treating bacterial infections and represent a promising alternative or complement to antibiotic treatment. Yet, other alternatives exist, [...] Read more.
Due to the extensive use of antibiotics, the increase of infections caused by antibiotic-resistant bacteria is now a global health concern. Phages have proven useful for treating bacterial infections and represent a promising alternative or complement to antibiotic treatment. Yet, other alternatives exist, such as bacteria-produced non-replicative protein complexes that can kill their targeted bacteria by puncturing their membrane (Tailocins). To expand the repertoire of Tailocins available, we suggest a new approach that transforms phages into Tailocins. Here, we genetically engineered the virulent Ackermannviridae phage S117, as well as temperate phages Fels-1, -2 and Gifsy-1 and -2, targeting the food pathogen Salmonella, by deleting the portal vertex or major capsid gene using CRISPR-Cas9. We report the production of Tailocin particles from engineered virulent and temperate phages able to kill their native host. Our work represents a steppingstone that taps into the huge diversity of phages and transforms them into versatile puncturing new antimicrobials. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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15 pages, 3659 KiB  
Article
New Phage-Derived Antibacterial Enzyme PolaR Targeting Rothia spp.
by Paulina Miernikiewicz, Jakub Barylski, Aleksandra Wilczak, Anna Dragoš, Izabela Rybicka, Sophia Bałdysz, Aleksander Szymczak, Iztok Dogsa, Kostiantyn Rokush, Marek Adam Harhala, Jarosław Ciekot, Stanisław Ferenc, Jan Gnus, Wojciech Witkiewicz and Krystyna Dąbrowska
Cells 2023, 12(15), 1997; https://doi.org/10.3390/cells12151997 - 04 Aug 2023
Cited by 1 | Viewed by 1436
Abstract
Rothia is an opportunistic pathogen, particularly life-threatening for the immunocompromised. It is associated with pneumonia, endocarditis, peritonitis and many other serious infections, including septicemia. Of note, Rothia mucilaginousa produces metabolites that support and increase overgrowth of Pseudomonas aeruginosa, one of the ESKAPE [...] Read more.
Rothia is an opportunistic pathogen, particularly life-threatening for the immunocompromised. It is associated with pneumonia, endocarditis, peritonitis and many other serious infections, including septicemia. Of note, Rothia mucilaginousa produces metabolites that support and increase overgrowth of Pseudomonas aeruginosa, one of the ESKAPE bacteria. Endolysins are considered as antibacterial enzymes derived from bacteriophages that selectively and efficiently kill susceptible bacteria without harming human cells or the normal microbiome. Here, we applied a computational analysis of metagenomic sequencing data of the gastric mucosa phageome extracted from human patients’ stomach biopsies. A selected candidate anti-Rothia sequence was produced in an expression system, purified and confirmed as a Rothia mucilaginosa- and Rothia dentocariosa-specific endolysin PolaR, able to destroy bacterial cells even when aggregated, as in a biofilm. PolaR had no cytotoxic or antiproliferative effects on mammalian cells. PolaR is the first described endolysin selectively targeting Rothia species, with a high potential to combat infections caused by Rothia mucilaginosa and Rothia dentocariosa, and possibly other bacterial groups. PolaR is the first antibacterial enzyme selected from the gastric mucosa phageome, which underlines the biological complexity and probably underestimated biological role of the phageome in the human gastric mucosa. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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18 pages, 3928 KiB  
Article
Accessing the In Vivo Efficiency of Clinically Isolated Phages against Uropathogenic and Invasive Biofilm-Forming Escherichia coli Strains for Phage Therapy
by Swapnil Ganesh Sanmukh, Joana Admella, Laura Moya-Andérico, Tamás Fehér, Betsy Verónica Arévalo-Jaimes, Núria Blanco-Cabra and Eduard Torrents
Cells 2023, 12(3), 344; https://doi.org/10.3390/cells12030344 - 17 Jan 2023
Cited by 6 | Viewed by 3119
Abstract
Escherichia coli is one of the most common members of the intestinal microbiota. Many of its strains are associated with various inflammatory infections, including urinary or gut infections, especially when displaying antibiotic resistance or in patients with suppressed immune systems. According to recent [...] Read more.
Escherichia coli is one of the most common members of the intestinal microbiota. Many of its strains are associated with various inflammatory infections, including urinary or gut infections, especially when displaying antibiotic resistance or in patients with suppressed immune systems. According to recent reports, the biofilm-forming potential of E. coli is a crucial factor for its increased resistance against antibiotics. To overcome the limitations of using antibiotics against resistant E. coli strains, the world is turning once more towards bacteriophage therapy, which is becoming a promising candidate amongst the current personalized approaches to target different bacterial infections. Although matured and persistent biofilms pose a serious challenge to phage therapy, they can still become an effective alternative to antibiotic treatment. Here, we assess the efficiency of clinically isolated phages in phage therapy against representative clinical uropathogenic and invasive biofilm-forming E. coli strains. Our results demonstrate that irrespective of host specificity, bacteriophages producing clear plaques with a high burst size, and exhibiting depolymerizing activity, are good candidates against biofilm-producing E. coli pathogens as verified from our in vitro and in vivo experiments using Galleria mellonella where survival was significantly increased for phage-therapy-treated larvae. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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Review

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24 pages, 2933 KiB  
Review
Phage Endolysins: Advances in the World of Food Safety
by Amina Nazir, Xiaohui Xu, Yuqing Liu and Yibao Chen
Cells 2023, 12(17), 2169; https://doi.org/10.3390/cells12172169 - 29 Aug 2023
Cited by 1 | Viewed by 2773
Abstract
As antimicrobial resistance continues to escalate, the exploration of alternative approaches to safeguard food safety becomes more crucial than ever. Phage endolysins are enzymes derived from phages that possess the ability to break down bacterial cell walls. They have emerged as promising antibacterial [...] Read more.
As antimicrobial resistance continues to escalate, the exploration of alternative approaches to safeguard food safety becomes more crucial than ever. Phage endolysins are enzymes derived from phages that possess the ability to break down bacterial cell walls. They have emerged as promising antibacterial agents suitable for integration into food processing systems. Their application as food preservatives can effectively regulate pathogens, thus contributing to an overall improvement in food safety. This review summarizes the latest techniques considering endolysins’ potential for food safety. These techniques include native and engineered endolysins for controlling bacterial contamination at different points within the food production chain. However, we find that characterizing endolysins through in vitro methods proves to be time consuming and resource intensive. Alternatively, the emergence of advanced high-throughput sequencing technology necessitates the creation of a robust computational framework to efficiently characterize recently identified endolysins, paving the way for future research. Machine learning encompasses potent tools capable of analyzing intricate datasets and pattern recognition. This study briefly reviewed the use of these industry 4.0 technologies for advancing the research in food industry. We aimed to provide current status of endolysins in food industry and new insights by implementing these industry 4.0 strategies revolutionizes endolysin development. It will enhance food safety, customization, efficiency, transparency, and collaboration while reducing regulatory hurdles and ensuring timely product availability. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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17 pages, 1351 KiB  
Review
Stability Considerations for Bacteriophages in Liquid Formulations Designed for Nebulization
by Rohan Flint, Daniel R. Laucirica, Hak-Kim Chan, Barbara J. Chang, Stephen M. Stick and Anthony Kicic
Cells 2023, 12(16), 2057; https://doi.org/10.3390/cells12162057 - 12 Aug 2023
Cited by 2 | Viewed by 1413
Abstract
Pulmonary bacterial infections present a significant health risk to those with chronic respiratory diseases (CRDs) including cystic fibrosis (CF) and chronic-obstructive pulmonary disease (COPD). With the emergence of antimicrobial resistance (AMR), novel therapeutics are desperately needed to combat the emergence of resistant superbugs. [...] Read more.
Pulmonary bacterial infections present a significant health risk to those with chronic respiratory diseases (CRDs) including cystic fibrosis (CF) and chronic-obstructive pulmonary disease (COPD). With the emergence of antimicrobial resistance (AMR), novel therapeutics are desperately needed to combat the emergence of resistant superbugs. Phage therapy is one possible alternative or adjunct to current antibiotics with activity against antimicrobial-resistant pathogens. How phages are administered will depend on the site of infection. For respiratory infections, a number of factors must be considered to deliver active phages to sites deep within the lung. The inhalation of phages via nebulization is a promising method of delivery to distal lung sites; however, it has been shown to result in a loss of phage viability. Although preliminary studies have assessed the use of nebulization for phage therapy both in vitro and in vivo, the factors that determine phage stability during nebulized delivery have yet to be characterized. This review summarizes current findings on the formulation and stability of liquid phage formulations designed for nebulization, providing insights to maximize phage stability and bactericidal activity via this delivery method. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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17 pages, 1140 KiB  
Review
What’s in a Name? An Overview of the Proliferating Nomenclature in the Field of Phage Lysins
by Roberto Vázquez and Yves Briers
Cells 2023, 12(15), 2016; https://doi.org/10.3390/cells12152016 - 07 Aug 2023
Cited by 1 | Viewed by 1428
Abstract
In the last few years, the volume of research produced on phage lysins has grown spectacularly due to the interest in using them as alternative antimicrobials. As a result, a plethora of naming customs has sprouted among the different research groups devoted to [...] Read more.
In the last few years, the volume of research produced on phage lysins has grown spectacularly due to the interest in using them as alternative antimicrobials. As a result, a plethora of naming customs has sprouted among the different research groups devoted to them. While the naming diversity accounts for the vitality of the topic, on too many occasions it also creates some confusion and lack of comparability between different works. This article aims at clarifying the ambiguities found among names referring to phage lysins. We do so by tackling the naming customs historically, framing their original adoption, and employing a semantic classification to facilitate their discussion. We propose a periodization of phage lysin research that begins at the discovery era, in the early 20th century, enriches with a strong molecular biology period, and grows into a current time of markedly applied research. During these different periods, names referring to the general concepts surrounding lysins have been created and adopted, as well as other more specific terms related to their structure and function or, finally, names that have been coined for the antimicrobial application and engineering of phage lysins. Thus, this article means to serve as an invitation to the global lysin community to take action and discuss a widely supported, standardized nomenclature. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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25 pages, 1255 KiB  
Review
Phage Interactions with the Nervous System in Health and Disease
by Adam Jędrusiak, Wojciech Fortuna, Joanna Majewska, Andrzej Górski and Ewa Jończyk-Matysiak
Cells 2023, 12(13), 1720; https://doi.org/10.3390/cells12131720 - 26 Jun 2023
Cited by 2 | Viewed by 2084
Abstract
The central nervous system manages all of our activities (e.g., direct thinking and decision-making processes). It receives information from the environment and responds to environmental stimuli. Bacterial viruses (bacteriophages, phages) are the most numerous structures occurring in the biosphere and are also found [...] Read more.
The central nervous system manages all of our activities (e.g., direct thinking and decision-making processes). It receives information from the environment and responds to environmental stimuli. Bacterial viruses (bacteriophages, phages) are the most numerous structures occurring in the biosphere and are also found in the human organism. Therefore, understanding how phages may influence this system is of great importance and is the purpose of this review. We have focused on the effect of natural bacteriophages in the central nervous system, linking them to those present in the gut microbiota, creating the gut-brain axis network, as well as their interdependence. Importantly, based on the current knowledge in the field of phage application (e.g., intranasal) in the treatment of bacterial diseases associated with the brain and nervous system, bacteriophages may have significant therapeutic potential. Moreover, it was indicated that bacteriophages may influence cognitive processing. In addition, phages (via phage display technology) appear promising as a targeted therapeutic tool in the treatment of, among other things, brain cancers. The information collected and reviewed in this work indicates that phages and their impact on the nervous system is a fascinating and, so far, underexplored field. Therefore, the aim of this review is not only to summarize currently available information on the association of phages with the nervous system, but also to stimulate future studies that could pave the way for novel therapeutic approaches potentially useful in treating bacterial and non-bacterial neural diseases. Full article
(This article belongs to the Special Issue Bacteriophages and Their Enzymes as Antibacterial Agents)
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