scholarly journals Promises and pitfalls of in vivo evolution to improve phage therapy

2019 ◽  
Author(s):  
James J Bull ◽  
Bruce R. Levin ◽  
Ian J. Molineux
Keyword(s):  
Bacterial Infections ◽  
Computational Models ◽  
Phage Therapy ◽  
Informed Choice ◽  
Resistant Bacteria ◽  
Prior History ◽  
Therapeutic Success ◽  
History Of ◽  
History Of Use

Abstract(Background) Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections. Phages lack the broad host ranges of antibiotics, so individual phages are often used with no prior history of use in treatment. Therapeutic phages are thus often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. It is possible that better treatment outcomes might be obtained from an informed choice of phages. Here we consider whether phages used to treat the bacterial infection in a patient might specifically evolve to improve treatment. Phages recovered from the patient could then serve as a source of improved phages or cocktails for use on subsequent patients. (Methods) With the aid of mathematical and computational models, we explore this possibility for four phage properties expected to promote therapeutic success: in vivo growth, phage decay rate, overcoming resistant bacteria, and enzyme activity to degrade protective bacterial layers. (Results) Phage evolution only sometimes works in favor of treatment, and even in those cases, intrinsic phage dynamics in the patient are usually not ideal. An informed use of phages is invariably superior to reliance on within-host evolution and dynamics, although the extent of this benefit varies with the application.

scholarly journals Promises and Pitfalls of In Vivo Evolution to Improve Phage Therapy

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1083 ◽  
Author(s):  
James J. Bull ◽  
Bruce R. Levin ◽  
Ian J. Molineux
Keyword(s):  
Decay Rate ◽  
Bacterial Infections ◽  
Computational Models ◽  
Phage Therapy ◽  
Treatment Success ◽  
Medical Intervention ◽  
Resistant Bacteria ◽  
Therapeutic Success ◽  
Phage Growth

Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections, a medical intervention long abandoned in the West but now experiencing a revival. Currently, therapeutic phages are often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. Better treatment might result from an informed choice of phages. Here we consider whether phages used to treat the bacterial infection in a patient may specifically evolve to improve treatment on that patient or benefit subsequent patients. With mathematical and computational models, we explore in vivo evolution for four phage properties expected to influence therapeutic success: generalized phage growth, phage decay rate, excreted enzymes to degrade protective bacterial layers, and growth on resistant bacteria. Within-host phage evolution is strongly aligned with treatment success for phage decay rate but only partially aligned for phage growth rate and growth on resistant bacteria. Excreted enzymes are mostly not selected for treatment success. Even when evolution and treatment success are aligned, evolution may not be rapid enough to keep pace with bacterial evolution for maximum benefit. An informed use of phages is invariably superior to naive reliance on within-host evolution.

Efficacy of experimental phage therapies in livestock

2020 ◽  
Vol 21 (1) ◽  
pp. 69-83 ◽  
Author(s):  
Marta Dec ◽  
Andrzej Wernicki ◽  
Renata Urban-Chmiel
Keyword(s):  
Bacterial Infections ◽  
Phage Therapy ◽  
Resistant Bacteria ◽  
Form Of Life ◽  
Drug Resistant Bacteria ◽  
Experimental Therapies ◽  
History Of ◽  
Experimental Treatments ◽  
Human Infections ◽  
Life On Earth

AbstractBacteriophages are the most abundant form of life on earth and are present everywhere. The total number of bacteriophages has been estimated to be 1032 virions. The main division of bacteriophages is based on the type of nucleic acid (DNA or RNA) and on the structure of the capsid. Due to the significant increase in the number of multi-drug-resistant bacteria, bacteriophages could be a useful tool as an alternative to antibiotics in experimental therapies to prevent and to control bacterial infections in people and animals. The aim of this review was to discuss the history of phage therapy as a replacement for antibiotics, in response to EU regulations prohibiting the use of antibiotics in livestock, and to present current examples and results of experimental phage treatments in comparison to antibiotics. The use of bacteriophages to control human infections has had a high success rate, especially in mixed infections caused mainly by Staphylococcus, Pseudomonas, Enterobacter, and Enterococcus. Bacteriophages have also proven to be an effective tool in experimental treatments for combating diseases in livestock.

scholarly journals Quantitative Models of Phage-Antibiotics Combination Therapy

2019 ◽  
Author(s):  
Rogelio A. Rodriguez-Gonzalez ◽  
Chung-Yin Leung ◽  
Benjamin K. Chan ◽  
Paul E. Turner ◽  
Joshua S. Weitz
Keyword(s):  
Combination Therapy ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
System Level ◽  
Global Public Health ◽  
Bacteriophage Therapy ◽  
Therapeutic Success ◽  
Health Crisis ◽  
Bacterial Mutants

AbstractThe spread of multi-drug resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or “phage therapy”) constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage and antibiotics for in-vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage-sensitive (and antibiotic resistant) and one which is antibiotic-sensitive (and phage-resistant). We find that combination therapy outperforms either phage or antibiotic alone, and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at sub-inhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in-silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes.

scholarly journals Tackling Virulence of Pseudomonas aeruginosa by the Natural Furanone Sotolon

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 871
Author(s):  
Mohammed F. Aldawsari ◽  
El-Sayed Khafagy ◽  
Ahmed Al Saqr ◽  
Ahmed Alalaiwe ◽  
Hisham A. Abbas ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Bacterial Infections ◽  
Therapeutic Agent ◽  
Bacterial Resistance ◽  
Inhibitory Concentration ◽  
Bacterial Biofilm ◽  
Resistant Bacteria ◽  
Resistance Development

The bacterial resistance development due to the incessant administration of antibiotics has led to difficulty in their treatment. Natural adjuvant compounds can be co-administered to hinder the pathogenesis of resistant bacteria. Sotolon is the prevailing aromatic compound that gives fenugreek its typical smell. In the current work, the anti-virulence activities of sotolon on Pseudomonas aeruginosa have been evaluated. P. aeruginosa has been treated with sotolon at sub-minimum inhibitory concentration (MIC), and production of biofilm and other virulence factors were assessed. Moreover, the anti-quorum sensing (QS) activity of sotolon was in-silico evaluated by evaluating the affinity of sotolon to bind to QS receptors, and the expression of QS genes was measured in the presence of sotolon sub-MIC. Furthermore, the sotolon in-vivo capability to protect mice against P. aeruginosa was assessed. Significantly, sotolon decreased the production of bacterial biofilm and virulence factors, the expression of QS genes, and protected mice from P. aeruginosa. Conclusively, the plant natural substance sotolon attenuated the pathogenicity of P. aeruginosa, locating it as a plausible potential therapeutic agent for the treatment of its infections. Sotolon can be used in the treatment of bacterial infections as an alternative or adjuvant to antibiotics to combat their high resistance to antibiotics.

Severe Hemolytic Reaction Due to Anti-JK3

1999 ◽  
Vol 123 (10) ◽  
pp. 949-951
Author(s):  
Carol S. Marshall ◽  
Denis Dwyre ◽  
Robin Eckert ◽  
Liisa Russell
Keyword(s):  
The United States ◽  
Cell Phenotype ◽  
Prior History ◽  
Ethnic Variability ◽  
Hemolytic Transfusion Reaction ◽  
History Of ◽  
Rare Phenotype ◽  
Antibody Screen

Abstract A 35-year-old gravida 3, para 3 Filipino woman with a negative antibody screen, no prior history of transfusion, and no hemolytic disease of the newborn in her children suffered a massive postpartum hemorrhage requiring transfusion. A severe hemolytic transfusion reaction occurred 5 days after delivery. Subsequently, a panagglutinin on a routine antibody identification panel was identified as anti-Jk3. The patient's red blood cell phenotype was Jk(a−b−) and all of her children were Jk(a−b+), yet the antibody that formed reacted with equal strength against all Jka- or Jkb-positive cells. The rare Jk(a−b−) phenotype is more common in Polynesians. Anti-Jk3, like other Kidd system antibodies, is difficult to detect because in vivo production may be absent between provocative episodes and because these antibodies often show weak in vitro reactions. The increasing numbers of Pacific Islanders in the United States could result in more frequent encounters with this rare phenotype. Increased awareness of ethnic variability in blood phenotypes and of the capricious nature of Kidd antibodies can help pathologists and technologists deal more effectively with these cases.

scholarly journals Bacteriophages: the possible solution to treat infections caused by pathogenic bacteria

2017 ◽  
Vol 63 (11) ◽  
pp. 865-879 ◽  
Author(s):  
Ayman El-Shibiny ◽  
Salma El-Sahhar
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Phage Therapy ◽  
Multidrug Resistant ◽  
Clinical Applications ◽  
Western World ◽  
Resistant Bacteria ◽  
Vaccine Production ◽  
Bacterial Populations ◽  
Antibiotic Resistant

Since their discovery in 1915, bacteriophages have been used to treat bacterial infections in animals and humans because of their unique ability to infect their specific bacterial hosts without affecting other bacterial populations. The research carried out in this field throughout the 20th century, largely in Georgia, part of USSR and Poland, led to the establishment of phage therapy protocols. However, the discovery of penicillin and sulfonamide antibiotics in the Western World during the 1930s was a setback in the advancement of phage therapy. The misuse of antibiotics has reduced their efficacy in controlling pathogens and has led to an increase in the number of antibiotic-resistant bacteria. As an alternative to antibiotics, bacteriophages have become a topic of interest with the emergence of multidrug-resistant bacteria, which are a threat to public health. Recent studies have indicated that bacteriophages can be used indirectly to detect pathogenic bacteria or directly as biocontrol agents. Moreover, they can be used to develop new molecules for clinical applications, vaccine production, drug design, and in the nanomedicine field via phage display.

scholarly journals Validation Metrics for Deterministic and Probabilistic Data

2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Kathryn A. Maupin ◽  
Laura P. Swiler ◽  
Nathan W. Porter
Keyword(s):  
Computational Models ◽  
Modern Science ◽  
Probabilistic Data ◽  
Validation Metrics ◽  
Physical Experiments ◽  
History Of ◽  
Computational Modeling And Simulation ◽  
History Of Use ◽  
The Impact ◽  
Application Specific

Computational modeling and simulation are paramount to modern science. Computational models often replace physical experiments that are prohibitively expensive, dangerous, or occur at extreme scales. Thus, it is critical that these models accurately represent and can be used as replacements for reality. This paper provides an analysis of metrics that may be used to determine the validity of a computational model. While some metrics have a direct physical meaning and a long history of use, others, especially those that compare probabilistic data, are more difficult to interpret. Furthermore, the process of model validation is often application-specific, making the procedure itself challenging and the results difficult to defend. We therefore provide guidance and recommendations as to which validation metric to use, as well as how to use and decipher the results. An example is included that compares interpretations of various metrics and demonstrates the impact of model and experimental uncertainty on validation processes.

scholarly journals Effects of Sequential and Simultaneous Applications of Bacteriophages on Populations of Pseudomonas aeruginosaIn Vitroand in Wax Moth Larvae

2012 ◽  
Vol 78 (16) ◽  
pp. 5646-5652 ◽  
Author(s):  
Alex R. Hall ◽  
Daniel De Vos ◽  
Ville-Petri Friman ◽  
Jean-Paul Pirnay ◽  
Angus Buckling
Keyword(s):  
Bacterial Infections ◽  
Phage Therapy ◽  
Phage Type ◽  
Resistant Bacteria ◽  
Short Term ◽  
Short Term Treatment ◽  
Simultaneous Application ◽  
Content Type ◽  
Wax Moth

ABSTRACTInterest in using bacteriophages to treat bacterial infections (phage therapy) is growing, but there have been few experiments comparing the effects of different treatment strategies on both bacterial densities and resistance evolution. While it is established that multiphage therapy is typically more effective than the application of a single phage type, it is not clear if it is best to apply phages simultaneously or sequentially. We tried single- and multiphage therapy againstPseudomonas aeruginosaPAO1in vitro, using different combinations of phages either simultaneously or sequentially. Across different phage combinations, simultaneous application was consistently equal or superior to sequential application in terms of reducing bacterial population density, and there was no difference (on average) in terms of minimizing resistance. Phage-resistant bacteria emerged in all experimental treatments and incurred significant fitness costs, expressed as reduced growth rate in the absence of phages. Finally, phage therapy increased the life span of wax moth larvae infected withP. aeruginosa, and a phage cocktail was the most effective short-term treatment. When the ratio of phages to bacteria was very high, phage cocktails cured otherwise lethal infections. These results suggest that while adding all available phages simultaneously tends to be the most successful short-term strategy, there are sequential strategies that are equally effective and potentially better over longer time scales.

scholarly journals Phage Therapy -- Everything Old Is New again

2006 ◽  
Vol 17 (5) ◽  
pp. 297-306 ◽  
Author(s):  
Andrew M Kropinski
Keyword(s):  
Bacterial Infections ◽  
Phage Therapy ◽  
Therapeutic Modality ◽  
Resistant Bacteria ◽  
Pathogenic Potential ◽  
Microbial Genetics ◽  
Antibiotic Resistant ◽  
Vector Systems ◽  
Variable Success ◽  
Bacterial Viruses

The study of bacterial viruses (bacteriophages or phages) proved pivotal in the nascence of the disciplines of molecular biology and microbial genetics, providing important information on the central processes of the bacterial cell (DNA replication, transcription and translation) and on how DNA can be transferred from one cell to another. As a result of the pioneering genetics studies and modern genomics, it is now known that phages have contributed to the evolution of the microbial cell and to its pathogenic potential. Because of their ability to transmit genes, phages have been exploited to develop cloning vector systems. They also provide a plethora of enzymes for the modern molecular biologist. Until the introduction of antibiotics, phages were used to treat bacterial infections (with variable success). Western science is now having to re-evaluate the application of phage therapy -- a therapeutic modality that never went out of vogue in Eastern Europe -- because of the emergence of an alarming number of antibiotic-resistant bacteria. The present article introduces the reader to phage biology, and the benefits and pitfalls of phage therapy in humans and animals.

scholarly journals Bacteriophage therapy: experience from the Eliava Institute, Georgia

2008 ◽  
Vol 29 (2) ◽  
pp. 96 ◽  
Author(s):  
Nina Chanishvili ◽  
Richard Sharp
Keyword(s):  
Soviet Union ◽  
Former Soviet Union ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Effective Means ◽  
Resistant Bacteria ◽  
Bacteriophage Therapy ◽  
Antibiotic Resistant ◽  
Bacterial Diseases ◽  
Wide Range

The lysis of bacteria by bacteriophage was independently discovered by Frederick Twort and Felix d?Herelle but it was d?Herelle who proposed that bacteriophage might be applied to the control of bacterial diseases. Within the former Soviet Union (FSU), bacteriophage therapy was researched and applied extensively for the treatment of a wide range of bacterial infections. In the West, however, it was not explored with the same enthusiasm and was eventually discarded with the arrival of antibiotics. However, the increase in the incidence of multi-antibiotic-resistant bacteria and the absence of effective means for their control has led to increasing international interest in phage therapy and in the long experience of the Eliava Institute. The Eliava Institute of Bacteriophage, Microbiology and Virology (IBMV), which celebrates its 85th anniversary in 2008, was founded in Tbilisi in 1923 through the joint efforts of d?Herelle and the Georgian microbiologist, George Eliava.

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