Phage Therapy: Eco-Physiological Pharmacology

Bacterial virus use as antibacterial agents, in the guise of what is commonly known as phage therapy, is an inherently physiological, ecological, and also pharmacological process. Physiologically we can consider metabolic properties of phage infections of bacteria and variation in those properties as a function of preexisting bacterial states. In addition, there are patient responses to pathogenesis, patient responses to phage infections of pathogens, and also patient responses to phage virions alone. Ecologically, we can consider phage propagation, densities, distribution (within bodies), impact on body-associated microbiota (as ecological communities), and modification of the functioning of body “ecosystems” more generally. These ecological and physiological components in many ways represent different perspectives on otherwise equivalent phenomena. Comparable to drugs, one also can view phages during phage therapy in pharmacological terms. The relatively unique status of phages within the context of phage therapy as essentially replicating antimicrobials can therefore result in a confluence of perspectives, many of which can be useful towards gaining a better mechanistic appreciation of phage therapy, as I consider here. Pharmacology more generally may be viewed as a discipline that lies at an interface between organism-associated phenomena, as considered by physiology, and environmental interactions as considered by ecology.

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Sensitivity of Staphylococcus aureus cultures of different biological origin to commercial bacteriophages and phages of Staphylococcus aureus var. bovis

Veterinary World ◽

10.14202/vetworld.2021.1588-1593 ◽

2021 ◽

pp. 1588-1593

Author(s):

Yulia Horiuk ◽

Mykola Kukhtyn ◽

Serhiy Kernychnyi ◽

Svitlana Laiter-Moskaliuk ◽

Sergiy Prosyanyi ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Staphylococcus Epidermidis ◽

Dairy Products ◽

Antibacterial Agents ◽

Phage Therapy ◽

Dairy Farms ◽

Mammary Glands ◽

Dairy Herds ◽

Food Markets ◽

Biological Origin

Background and Aim: Mastitis, an inflammation of the mammary gland, is an ongoing problem in dairy herds. In this study, we determined the sensitivity of Staphylococcus aureus cultures of different biological origins to commercial bacteriophages and phages of S. aureus var. bovis which were isolated on dairy farms, to create a drug for the treatment of mastitis in cows. Materials and Methods: We used cultures of S. aureus isolated from different habitats, and other types of staphylococci isolated on dairy farms. As antibacterial agents, the commercially available bacteriophages staphylococcal bacteriophage and Intestifag and field strains of phages Phage SAvB07, Phage SAvB08, Phage SAvB12, and Phage SAvB14 were used. Evaluation of their lytic properties was performed using the drip method. Results: The drug Intestifag lysed cultures isolated from human habitats and archival strains of S. aureus No.209-P and S. aureus (ATCC 25923) in 91.8%–100% of cases. Staphylococcal bacteriophage killed 3.6 times fewer cultures of S. aureus isolated from humans than Intestifag and did not affect the growth of archival strains. Neither drug lysed cultures isolated from cows or cultures isolated from dairy products sold in agri-food markets. Phage SAvB14 lysed 92.7±8.3% of S. aureus isolated from the mammary glands of cows and 69.2±6.4% of cultures isolated from dairy products sold in agri-food markets. Phage SAvB12, Phage SAvB08, and Phage SAvB07 lysed 1.2-1.7 times fewer cultures isolated from the mammary glands of cows and 6-18 times fewer cultures isolated from dairy products, compared with Phage SAvB14. Phages of S. aureus var. bovis can infect staphylococcal species such as Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus saprophyticus, and Staphylococcus xylosus. The widest range of hosts was found for Phage SAvB14, which indicates its polyvalence. Conclusion: The biological origin of staphylococcal strains must be considered when developing effective phage therapy. Phage SAvB14 appears to be a good candidate for the development of a drug for the treatment of mastitis in cows.

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Potential application of phage therapy for prophylactic treatment against Pseudomonasaeruginosabiofilm Infections

10.1101/404145 ◽

2018 ◽

Author(s):

Aditi Gurkar ◽

Deepak Balasubramanian ◽

Jayasheela Manur ◽

Kalai Mathee

Keyword(s):

Biofilm Formation ◽

Defense Mechanisms ◽

Antibacterial Agents ◽

Prophylactic Treatment ◽

Phage Therapy ◽

Planktonic Cells ◽

Biofilm Growth ◽

Cellular Defense ◽

Bacterial Mass

ABSTRACTThe majority of the microbial activity in humans is in the form of biofilms, i.e., an exopolysaccharide-enclosed bacterial mass. Unlike planktonic cells and the cells on the surface of the biofilm, the biofilm-embedded cells are more resistant to the effects of the antibiotics and the host cellular defense mechanisms. A combination of biofilm growth and inherent resistance prevents effective antibiotic treatment ofPseudomonas aeruginosainfections including those in patients with cystic fibrosis. Antibiotic resistance has led to an increasing interest in alternative modalities of treatment. Thus, phages that multiplyin situand in the presence of susceptible hosts can be used as natural, self-limiting, and profoundly penetrating antibacterial agents. The objective of this study is to identify active phages against a collection ofP. aeruginosaisolates (PCOR strains) including the prototype PAO1 and the isogenic constitutively alginate-producing PDO300 strains. These PCOR strains were tested against six phages (P105, P134, P140, P168, P175B, and P182). The analysis shows 69 % of the PCOR isolates are sensitive and the rest are resistant to all six phages. These phages were then tested for their ability to inhibit biofilm formation using a modified biofilm assay. The analysis demonstrated that the sensitive strains showed increased resistance, but none of the susceptible strains from the initial screening were resistant. Using the minimum biofilm eradication concentration (MBEC) assay for biofilm formation, the biofilm eradication ability of the phages was tested. The data showed that a higher volume of phage was required to eradicate preformed biofilms than the amount required to prevent colonization of planktonic cells. This data supports the idea of phage therapy more as a prophylactic treatment.

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Microbial Arsenal of Antiviral Defenses – Part I

Biochemistry (Moscow) ◽

10.1134/s0006297921030081 ◽

2021 ◽

Vol 86 (3) ◽

pp. 319-337

Author(s):

Artem B. Isaev ◽

Olga S. Musharova ◽

Konstantin V. Severinov

Keyword(s):

Small Molecules ◽

Phage Therapy ◽

Phage Infection ◽

Dna Modification ◽

Bacterial Cells ◽

Host Defenses ◽

Microbial Genomes ◽

Broad Application ◽

Phage Propagation

Abstract Bacteriophages or phages are viruses that infect bacterial cells (for the scope of this review we will also consider viruses that infect Archaea). Constant threat of phage infection is a major force that shapes evolution of the microbial genomes. To withstand infection, bacteria had evolved numerous strategies to avoid recognition by phages or to directly interfere with phage propagation inside the cell. Classical molecular biology and genetic engineering have been deeply intertwined with the study of phages and host defenses. Nowadays, owing to the rise of phage therapy, broad application of CRISPR-Cas technologies, and development of bioinformatics approaches that facilitate discovery of new systems, phage biology experiences a revival. This review describes variety of strategies employed by microbes to counter phage infection, with a focus on novel systems discovered in recent years. First chapter covers defense associated with cell surface, role of small molecules, and innate immunity systems relying on DNA modification.

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Fighting Fire with Fire: Phage Potential for the Treatment of E. coli O157 Infection

Antibiotics ◽

10.3390/antibiotics7040101 ◽

2018 ◽

Vol 7 (4) ◽

pp. 101 ◽

Cited By ~ 3

Author(s):

Cristina Howard-Varona ◽

Dean Vik ◽

Natalie Solonenko ◽

Yueh-Fen Li ◽

M. Gazitua ◽

...

Keyword(s):

Shiga Toxin ◽

Bacterial Infections ◽

Antibacterial Agents ◽

Prophylactic Treatment ◽

Phage Therapy ◽

Toxin Production ◽

Prophage Induction ◽

E Coli ◽

Uremic Syndrome

Hemolytic–uremic syndrome is a life-threating disease most often associated with Shiga toxin-producing microorganisms like Escherichia coli (STEC), including E. coli O157:H7. Shiga toxin is encoded by resident prophages present within this bacterium, and both its production and release depend on the induction of Shiga toxin-encoding prophages. Consequently, treatment of STEC infections tend to be largely supportive rather than antibacterial, in part due to concerns about exacerbating such prophage induction. Here we explore STEC O157:H7 prophage induction in vitro as it pertains to phage therapy—the application of bacteriophages as antibacterial agents to treat bacterial infections—to curtail prophage induction events, while also reducing STEC O157:H7 presence. We observed that cultures treated with strictly lytic phages, despite being lysed, produce substantially fewer Shiga toxin-encoding temperate-phage virions than untreated STEC controls. We therefore suggest that phage therapy could have utility as a prophylactic treatment of individuals suspected of having been recently exposed to STEC, especially if prophage induction and by extension Shiga toxin production is not exacerbated.

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Phage Cocktail Development for Bacteriophage Therapy: Toward Improving Spectrum of Activity Breadth and Depth

Pharmaceuticals ◽

10.3390/ph14101019 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1019

Author(s):

Stephen T. Abedon ◽

Katarzyna M. Danis-Wlodarczyk ◽

Daniel J. Wozniak

Keyword(s):

Antibacterial Agents ◽

Phage Therapy ◽

Cross Resistance ◽

Phage Resistance ◽

Bacterial Strains ◽

Bacteriophage Therapy ◽

Commercial Development ◽

Phage Cocktail ◽

Bacterial Mutation ◽

Number Of Bacteria

Phage therapy is the use of bacterial viruses as antibacterial agents. A primary consideration for commercial development of phages for phage therapy is the number of different bacterial strains that are successfully targeted, as this defines the breadth of a phage cocktail’s spectrum of activity. Alternatively, phage cocktails may be used to reduce the potential for bacteria to evolve phage resistance. This, as we consider here, is in part a function of a cocktail’s ‘depth’ of activity. Improved cocktail depth is achieved through inclusion of at least two phages able to infect a single bacterial strain, especially two phages against which bacterial mutation to cross resistance is relatively rare. Here, we consider the breadth of activity of phage cocktails while taking both depth of activity and bacterial mutation to cross resistance into account. This is done by building on familiar algorithms normally used for determination solely of phage cocktail breadth of activity. We show in particular how phage cocktails for phage therapy may be rationally designed toward enhancing the number of bacteria impacted while also reducing the potential for a subset of those bacteria to evolve phage resistance, all as based on previously determined phage properties.

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Microbial Arsenal of Antiviral Defenses. Part II

Biochemistry (Moscow) ◽

10.1134/s0006297921040064 ◽

2021 ◽

Vol 86 (4) ◽

pp. 449-470

Author(s):

Artem B. Isaev ◽

Olga S. Musharova ◽

Konstantin V. Severinov

Keyword(s):

Small Molecules ◽

Phage Therapy ◽

Phage Infection ◽

Dna Modification ◽

Bacterial Cells ◽

Host Defenses ◽

Abortive Infection ◽

Microbial Genomes ◽

Infection Mechanisms ◽

Phage Propagation

Abstract Bacteriophages or phages are viruses that infect bacterial cells (for the scope of this review we will also consider viruses that infect Archaea). The constant threat of phage infection is a major force that shapes evolution of microbial genomes. To withstand infection, bacteria had evolved numerous strategies to avoid recognition by phages or to directly interfere with phage propagation inside the cell. Classical molecular biology and genetic engineering had been deeply intertwined with the study of phages and host defenses. Nowadays, owing to the rise of phage therapy, broad application of CRISPR-Cas technologies, and development of bioinformatics approaches that facilitate discovery of new systems, phage biology experiences a revival. This review describes variety of strategies employed by microbes to counter phage infection. In the first part defense associated with cell surface, roles of small molecules, and innate immunity systems relying on DNA modification were discussed. The second part focuses on adaptive immunity systems, abortive infection mechanisms, defenses associated with mobile genetic elements, and novel systems discovered in recent years through metagenomic mining.

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