Bacterial Viruses: Exploitation for Biocontrol and Therapeutics
Caister Academic Press
Aidan Coffey and Colin Buttimer
Cork Institute of Technology, Ireland and University College Cork, Ireland
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The potential of bacterial viruses (bacteriophages or phages) as antibacterial agents was recognised over a century ago. However, the success of antibiotic therapy from the 1940s onwards caused a general decline in the applications of phages as therapeutics. Nonetheless, recent decades have seen a disquieting proliferation of pathogenic bacteria resistant to multiple antibiotics commonly used in human and veterinary medicine, in turn leading towards a crisis in public health. The renewed exploration of phages and their molecular components for biocontrol and therapeutics offers a complementary approach for eliminating problematic bacteria across a range of sectors where bacterial infections and contaminations are a persistent problem.
Written by internationally-recognised scientists involved in the exploitation of bacterial viruses in diverse areas from around the world, this book provides comprehensive coverage of the current research in several phage applications for biocontrol of undesirable bacteria in human and veterinary medicine, horticulture, aquaculture and food. Chapters from the famous centres of phage therapy in Wrocław and Tbilisi detail some of the pioneering historical contributions to the topic. The book also examines the impact of phages on the human microbiome as well as the progress of research in phage engineering, phage enzymes, phage delivery systems, biodetection as well as intellectual property aspects.
Aimed at research scientists, advanced students and other professionals, this informative and up-to-date book is a recommended acquisition for all science and medical libraries.
Table of contents
1. An Overview of Current Phage Therapy: Challenges for Implementation
Naomi Hoyle, Randolph Fish, Nata Nakaidze, Satya Ambrose and Elizabeth Martin Kutter
Bacteriophages (phages) provide an increasingly recognised important option for the treatment of antibiotic resistant infections. This chapter will discuss key points in the history of phage therapy but will primarily focus on current advancements in phage therapeutics. We discuss compassionate use of phage therapy in the United States, Europe and Australia for severe infections caused by antibiotic resistant Acinetobacter baumannii, Carbapenemase-producing Klebsiella pneumoniae and multidrug resistant (MDR) Pseudomonas aeruginosa, among others. Challenges for implementation of phage therapy include the need for further development of therapeutic phage products in an appropriate manner for the current technology as well as clinical studies addressing gaps in the knowledge, especially in terms of dose, distribution, immune response, and legal framework, while drawing on the extensive history of phage used in other countries. Phage therapy has the potential to address a serious unmet need which has a significant economic impact, particularly the significant morbidity and mortality associated with antibiotic resistant infections.
2. Phage Therapy: The Pharmacology of Antibacterial Viruses
Katarzyna Danis-Wlodarczyk, Krystyna Dąbrowska and Stephen T. Abedon
Pharmacology can be differentiated into two key aspects, pharmacodynamics and pharmacokinetics. Pharmacodynamics describes a drug's impact on the body while pharmacokinetics describes the body's impact on a drug. Another way of understanding these terms is that pharmacodynamics is a description of both the positive and negative consequences of drugs attaining certain concentrations in the body while pharmacokinetics is concerned with our ability to reach and then sustain those concentrations. Unlike the drugs for which these concepts were developed, including antibiotics, the bacteriophages (or 'phages') that we consider in this chapter are not chemotherapeutics but instead are the viruses of bacteria. Here we review the pharmacology of these viruses, particularly as they can be employed to combat bacterial infections (phage therapy). Overall, an improved pharmacological understanding of phage therapy should allow for more informed development of phages as antibacterial 'drugs', allow for more rational post hoc debugging of phage therapy experiments, and encourage improved design of phage therapy protocols. Contrasting with antibiotics, however, phages as viruses impact individual bacterial cells as single virions rather than as swarms of molecules, and while they are killing bacteria, bacteriophages also can amplify phage numbers, in situ. Explorations of phage therapy pharmacology consequently can often be informed as well by basic principles of the ecological interactions between phages and bacteria as by study of the pharmacology of drugs. Bacteriophages in phage therapy thus can display somewhat unique as well as more traditional pharmacological aspects, as we consider here.
3. Human Gut Bacteriophages: Peacekeepers and Warriors at the Microbiota-Gut Interface
Susan Mills, Colin Hill and R. Paul Ross
The human gut phageome is not as well studied as its bacterial counterpart but studies to date strongly point to its role in generating microbiota diversity in early life and its contribution to microbiota fitness in adulthood. Kill-the-winner dynamics in the infant gut, governed by the bacteriophage (phage) lytic cycle, contribute to bacterial diversity and abundance levels, while piggy-back-the-winner dynamics in the adult gut is governed by the lysogenic cycle and contributes to bacterial fitness. However, increased phage abundance, presumably a result of prophage induction, has been associated with a number of diseases. The lysogenic-lytic switch appears to be a delicate balancing act and its full repertoire of triggers in this environment requires further investigation. Phages can also interact with host immunity and traverse the epithelial barrier. However, phage-bacteria-mammalian host interactions and phage-mammalian host interactions in the gut are only beginning to uncover how the phageome actually impacts health. In this review, we present the current state of the knowledge with regards to the cross-kingdom interactions that ensue. We also address the impact of the phageome on fecal microbiota transplantation and the potential of phage therapy for gut related diseases and its capacity to improve microbiota health. In evaluating the existing knowledge, we also shed light on gaps in the literature.
4. Polish Contribution to the Advancement of Phage Treatment in Humans
Maciej Żaczek, Beata Weber-Dąbrowska, Marzanna Łusiak-Szelachowska, Ryszard Międzybrodzki and Andrzej Górski
Polish research has helped to understand the significance of phage treatment in the new post-antibiotic reality. Its continuous growth over the decades distinguishes Poland from other countries, particularly from those located in the west of Europe and North America. Polish pioneering reports, although somewhat forgotten, remain one of the most compelling historical sources for researchers trying to piece together an incomplete picture of phage-related information. An ongoing phage renaissance constitutes an excellent opportunity to emphasize the significance of Polish efforts towards the development of phage therapy. Notably, the recent pandemic of COVID-19 demonstrates the importance of compassionate treatment in life-threatening circumstances. Such expanded access to phages has had a long tradition in Poland and shows robust insights into the clinical aspects of phage treatment in the last few decades.
5. Commercial Products for Human Phage Therapy
Nina Chanishvili and Marina Goderdzishvili
This article describes the development and distribution of early therapeutic bacteriophage (phage) products for the treatment of problematic bacterial infections before the advent of antibiotics. It details the beginnings of commercial phage production in Paris by Félix d'Hérelle in the 1920s leading subsequently to their production by L'Oréal, the manufacture of products in India to treat cholera, in Latin America to treat dysentery, and several in the USA by Ely Lilly to treat a range of infections up to the 1940s. It also discusses the various commercial products and the manufacturing approaches used to make them in the Republic of Georgia and throughout Russia from the Soviet period up to the present day, and details twenty-five commercial products for human phage therapy which are still officially registered there, most of which are widely purchased and used today. Genetic and metagenomic analysis of some of the latter products is discussed.
6. Application of Bacteriophages in Human Therapy: Recent Advances at the George Eliava Institute
Nina Chanishvili, Lia Nadareishvili, Elisabed Zaldastanishvili, Nana Balarjishvili and Mzia Kutateladze
This chapter describes a variety of recent compassionate-case phage therapy interventions performed using the expertise of the staff at the George Eliava Institute. The cases described include a variety of complex problematic infections involving various skin locations, those with cystic fibrosis, physiologically damaged diabetic feet, post-transplant conditions and urinary tract complications. The most remarkable developments are the positive findings following the execution of a small-scale human clinical trial, one which leads to the successful completion of a large-scale double-blind, randomised controlled human clinical trial aimed at eliminating problematic urinary tract infection in patients intended for transurethral resection of the prostate. The necessity for pre-adaption of existing phage cocktails to target a particular spectrum of infectious pathogens is also discussed.
7. Considerations for Using Bacteriophages in Plant Pathosystems
Aleksa Obradović, Jeffrey B. Jones, Botond Balogh and Katarina Gašić
Lytic bacteriophages (phages) have the potential for controlling susceptible bacteria in the rhizosphere or phyllosphere. The success of phage application in plant disease control requires that high populations of both phage and bacterium exist in order to initiate a chain reaction of bacterial lysis. Physical factors in natural environments such as the presence of biofilms that trap phages, low soil pH which inactivates phages, low rates of diffusion of phages in soil that prevent contact with target bacteria, and inactivation of phages upon exposure to ultraviolet (UV) light and desiccation, all impact successful use of phages in control of plant pathogenic bacteria. Other considerations relate to the bacterial strains which exist in nature. The bacterial species may have a low or high degree of variation in sensitivity to phages. Therefore, phage selection for field use requires careful monitoring of the targeted bacterial strains in the field due to the potential for strain variation and the likelihood for development of resistance to the deployed phages. Application timing has also been shown to be an important factor in improving the efficacy of phages. For instance, UV light is deleterious to phages and upon exposure phage populations plummet; therefore, evening applications of phages result in persistence on leaf surfaces for longer periods of time and may result in improved disease control. Extending the period of time that phages persist in the phyllosphere has been a major hurdle. Formulations have been identified which improve the persistence of phages on leaf surfaces; however, there is a need to identify superior formulations that extend the life on leaf surfaces from hours to days. Another strategy for maintaining high populations of phages has been to use non-pathogenic bacterial strains that are sensitive to the phage(s) or a closely related organism that does not cause disease on the plant host. Finally, phages may have value as part of an integrated management strategy.
8. Phage Biocontrol Applications in Food Production and Processing
Amit Vikram, Joelle Woolston and Alexander Sulakvelidze
Bacteriophages, or phages, are one of the most - if not the most - ubiquitous organisms on Earth. Interest in various practical applications of bacteriophages has been gaining momentum recently, with perhaps the most attention (and most regulatory approvals) focused on their use to improve food safety. This approach, termed 'phage biocontrol' or 'bacteriophage biocontrol', includes both pre- and post-harvest application of phages as well as decontamination of the food contact surfaces in food processing facilities. This chapter focuses on post-harvest applications of phage biocontrol, currently the most commonly used type of phage mediation. We also briefly describe various commercially available phage preparations and discuss the challenges still facing this novel yet promising approach.
9. Bacteriophage Therapy in Food Animals
Yongping Xu, Huijun Geng, Xiaoyu Li, Bingdong Wei, Cong Cong, Xiaowen Sun and Jibin Li
In animals destined for food use, bacteriophages have considerable potential, both for biocontrol of zoonotic pathogens such as Campylobacter, E. coli and Salmonella and also for therapeutic uses in animal diseases in much the same way as phages applied to treat human infections. Nevertheless, animal phage applications theoretically face less stringent regulations than those faced in the human context. The success of phage application for controlling target bacteria in animals generally has similar biological hurdles to those in other application areas. These include the phage(s) having a broad host range covering many strains within a bacterial species associated with a particular disease and the ability to physically survive long enough to reach the target area in the animal. Also, successful phage selection for biocontrol and therapeutic applications requires reliable monitoring of the epidemiology of strains or serotypes of the problematic bacterial species in the field. The explorations of phage therapy in the major food animals are discussed in this article and the findings outlined show these biological agents have considerable promise as part of an integrated disease management strategy in food animals.
10. Bacteriophages in Aquaculture
Yongping Xu, Hongyu Ren, Yongsheng Ma, Zhen Li, Xiaoyu Li, Lili Wang and Shuying Li
Aquaculture is one of the fastest-growing industries in the world and an essential part of economic development for numerous countries worldwide. However, large-scale intensive farming in this sector has led to increased occurrence of aquatic diseases leading to substantial financial losses. Additionally, the application of antibiotics and chemical drugs has become increasingly limited, which brings additional challenges to the prevention and treatment of diseases. Bacteriophages (phages) are bacterial viruses that naturally occur in nature and have the potential to be viable alternatives to chemical-based antibacterial agents. In this chapter, we will examine the progress and challenges towards the development of phage-based disease control for this industry.
11. Mycobacterium avium subspecies paratuberculosis: Are Mycobacteriophages the Answer?
Gillian Crowley, Colin Buttimer, Lorraine Endersen, Aidan Coffey and Jim O'Mahony
Johne's disease is a chronic wasting disease of ruminants and other animals. It impacts significantly on animal welfare and the livelihood of farmers. Due to the complexity of the causative organism (Mycobacterium avium ssp paratuberculosis), effective research into the detection and treatment of Johne's disease is problematic. Mycobacteriophages offer much hope on both fronts given their ubiquity in nature and their potential to target specific mycobacterial pathogens. This chapter traces the evolution of Johne's disease and catalogues the importance of mycobacteriophages. It also explores potential avenues of future research that may raise the hope of effectively treating the global problem of Johne's disease.
12. Phage Structural Antimicrobial Proteins
Sílvio B. Santos, Luís D.R. Melo and Hugo Oliveira
Bacterial polysaccharides (capsules, lipopolysaccharides, exopolysaccharides and peptidoglycan) play an important role in protection, by blocking the entry of antimicrobials, evading microbial defences and avoiding phage predation. To be able to enter the cell and replicate, phages rely mostly on two structural proteins to break down several host carbohydrate barriers. First, polysaccharide depolymerases are used by phages to bind and degrade the outermost polymers (capsules, lipopolysaccharides and exopolysaccharides) to reach the final host receptor. Second, the virion-associated lysins locally puncture small holes in the rigid cell wall (peptidoglycan) to enable the injection of the phage DNA into the cytoplasm, leading to the subsequent infection and replication of progeny phage. These polysaccharide depolymerases and virion-associated lysins are emerging as alternative antimicrobial agents to control pathogens by either reducing bacterial virulence or lysing bacteria, respectively. Herein we provide a comprehensive critical overview on the diversity of the structure, functions and biotechnological applications of these enzymes. This overview underlines the great potential of using phage structural proteins as anti-virulence and antimicrobial agents to control multidrug resistant pathogens in food, veterinary and human medicine.
13. Crystallographic Structure Determination of Bacteriophage Endolysins
Marta Sanz-Gaitero and Mark J. van Raaij
Bacteriophages produce endolysins that target and cleave the hosts peptidoglycan to release their progeny at the end of the infection cycle. These proteins can be used for the eradication of pathogenic bacteria, but also for their detection. Endolysins may contain a single catalytic domain or several domains, including a cell wall binding domain. To understand their function in detail and design mutated or chimeric molecules with novel properties, knowledge of their structures and detailed mechanisms is necessary. X-ray protein crystallography is an excellent method to obtain high-resolution structures of biological macromolecules, and here we describe the method and the folds of known endolysin domains.
14. Peptidoglycan Hydrolases from Phages of Gram-positive Bacteria
Sara Arroyo-Moreno, Colin Buttimer and Aidan Coffey
Bacterial resistance to conventional antibiotics has become an urgent healthcare issue worldwide. In this light, a renewed interest has emerged for therapy with bacteriophages, which are viruses that can specifically infect bacteria. These viruses encode different proteins that degrade specific bonds within the bacterial cell wall, both to inject their genomic material into the bacterial cells and to release the viral progeny: virion-associated hydrolases and endolysins, respectively. Elimination of Gram-positive pathogens with recombinant versions of phage enzymes represents a promising alternative to antibiotics. In some studies, these enzymes have been used successfully to eliminate/control bacterial pathogens in various anatomical locations in mice and other animal models. This review discusses the strategies developed to improve efficacy in terms of lytic activity and therapeutic delivery of these enzymes.
15. Developments and Opportunities of Bacteriophage Lytic Proteins for Therapeutics Against Gram-negative Pathogens
Diana Gutiérrez and Yves Briers
The globally increasing antimicrobial resistance levels urge for the introduction of novel classes of antimicrobials. In this regard, enzyme-based antibiotics (or enzybiotics) derived from phage lytic proteins represent a promising strategy. These enzymes kill bacteria through peptidoglycan degradation followed by osmotic lysis and come along with significant advantages such as a rapid bactericidal effect, a novel mode of action and a low probability of resistance development. They have been progressed significantly on the route for clinical application to treat infections caused by Gram-positive bacteria. The latter have a thick but easily accessible peptidoglycan layer. Gram-negative bacteria have been for long a no go zone for enzybiotics due to their protective outer membrane, principally excluding access to the thin peptidoglycan layer. This view has shifted drastically, particularly driven by the lack of remaining therapeutic options for infections caused by Gram-negatives. Diverse strategies grouped in three classes (phage lytic proteins with a natural intrinsic antibacterial activity, combination strategies with physical or chemical means and protein engineering) have been proposed and developed in the last decade, ranging from the conceptual to the preclinical level, and will be discussed in this chapter.
16. Genetically Engineered Bacteriophages
Rajesh Mamkulathil Devasia and Salim Manoharadas
With the advent of antibiotics, the use of bacteriophages (phages) as antimicrobial agents has been abandoned in the western world. However, the increasing prevalence of multi-drug resistant bacterial pathogens has resulted in a resurgence of research efforts to use phages as antimicrobials. A side effect of many antibiotics as well as of phage therapy is the release of cell wall components, e.g. endotoxins of Gram-negative bacteria, which mediate the general pathological aspects of septicaemia. In the last decade, several strategies based on genetically engineered lysis-deficient phages have been devised with the aim to avoid disintegration of the cell envelope but to kill the bacterial target. These studies indicated that killing-proficient but lysis-defective recombinant phages can be exploited as efficient antimicrobials with reduced side effects. Moreover, genetically engineered phages can be used to augment the antimicrobial efficacy of antibiotics and to reduce bacterial biofilms. Apart from these potential medical applications, modified phages have been used to detect bacterial pathogens in foodstuffs. Here, we provide a review of these studies and briefly discuss the prospects of genetically modified phage in medicine and industry.
17. Bacteriophage Encapsulation Using Spray Drying for Phage Therapy
Danish J. Malik
Exploiting the potential of bacteriophages for phage therapy is an exciting future prospect. However, in order to be successful, there is a pressing need for the manufacture of safe and efficacious phage drug products to treat patients. Scalable manufacture of phage biologics as a stable solid dry powder form is highly desirable and achievable using the process of spray drying. Spray drying of purified phage suspensions formulated with suitable excipients can be carried out in a single step with high process throughput and at relatively low cost. The resulting phage-containing powders can possess good storage shelf-life. The process allows control over the final phage dose in the powder and production of microparticles suitable for a variety of therapeutic uses. Spray dried powders may include different polymer formulations employing a multitude of different triggers for phage release at the target site including pH, enzymes, virulence factors etc. The activity of the phages in spray dried powders is adversely affected during spray drying due to desiccation and thermal stresses which need to be controlled. The choice of polymers, excipients and moisture content of the dry powders affects the material glass transition temperature and the stability of the phages during storage. The storage temperature and storage humidity are important factors affecting the stability of the phages in the dry powders. A quality by design (QbD) approach for phage drug product development needs to identify drug product characteristics that are critical to quality from the patient's perspective and translates them into the critical quality attributes (CQA) of the drug product. The relationship between the phage drug product CQAs and formulation development and spray drying process conditions are discussed in this chapter.
18. Practical Issues in Setting Up and Maintaining a Collection of Therapeutic Bacteriophages: the Finnish Experience
Saija Kiljunen, Jussi Tervonen and Mikael Skurnik
As part of our efforts to make bacteriophage (phage) therapy available to Finnish clinicians to treat patients suffering from infections caused by multi-drug resistant (MDR) bacterial pathogens, we have started a continually growing collection of phages against the most common MDR pathogens. The collection at present contains close to 400 phages that we characterize to select those that are suitable for therapeutic purposes. Roughly half of the phage genomes have been sequenced and analyzed. In this chapter, we describe some of the practical issues related to this project.
19. Commercialization of Phage Therapeutics: the Value of Intellectual Property and Patents
Fabien Palazzoli, Michael Koeris and Shawna McCallin
The time is ripe for a transition of bacteriophage (phage)-based products and services from a laboratory setting to commercial markets, yet there remain lingering doubts and questions as to if, how, and when this passage will occur. Exorbitant sunk costs to pay for the research and testing required to secure marketing authorizations for sales and distribution, and thus generate money, require high early-stage amounts of investment. The return on that initial investment, in turn, calls for high price tags and defence of intellectual property to ensure a certain market-share. Yet the market of antibacterials is conventionally low-cost, low-tech, and low-value, and phage therapies are furthermore not your standard pharmaceutical. Due to their historical discovery and use, many foundational aspects of phage R and D and applications fall in the public domain, therefore excluding patentability. Newer methods and techniques in areas in need of innovation for phage development, however, do offer a chance for intellectual property (IP) protection. While natural phages and phage combinations remain the most-heavily patented area, the volume of patent applications and their geographical origin show signs that there is indeed growing interest in protecting phage-based technologies, a key step before commercialization. The following chapter aims to provide the reader with a basic overview of different IP rights and agreements that are pertinent to the biotech industry and discuss their associated strengths and weaknesses. Current examples of product and business development in the areas of natural phages, genetically-modified phages, bioproduction and formulation, and therapeutic strategies will be highlighted. In the absence of evidence of efficacy from well-designed clinical trials, however, the value of patents and IP protection for phage products and their associated process is difficult to evaluate. The performance of phage therapy in the next few years will be decisive for sustainable and scalable commercialization.
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(EAN: 9781913652517 9781913652524 Subjects: [bacteriology] [medical microbiology] [microbiology] [molecular microbiology] [virology] )