#BIOPHAGES

Trained viruses prove more effective at fighting antibiotic resistance

Practice boosts phage potency in evolutionary battleground with deadly bacteria

UNIVERSITY OF CALIFORNIA - SAN DIEGO

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IMAGE: AFTER COMPETING IN FLASKS, DIFFERENT STRAINS OF BACTERIA ARE MOVED TO AGAR PLATES WHERE RESEARCHERS CAN EVALUATE THE "WINNER " BY COUNTING NUMBERS OF THOSE THAT SURVIVED. BACTERIA ARE IDENTIFIED WITH... view more 

CREDIT: MEYER LAB, UC SAN DIEGO

The threat of antibiotic resistance rises as bacteria continue to evolve to foil even the most powerful modern drug treatments. By 2050, antibiotic resistant-bacteria threaten to claim more than 10 million lives as existing therapies prove ineffective.

Bacteriophage, or "phage," have become a new source of hope against growing antibiotic resistance. Ignored for decades by western science, phages have become the subject of increasing research attention due to their capability to infect and kill bacterial threats.

A new project led by University of California San Diego Biological Sciences graduate student Joshua Borin, a member of Associate Professor Justin Meyer's laboratory, has provided evidence that phages that undergo special evolutionary training increase their capacity to subdue bacteria. Like a boxer in training ahead of a title bout, pre-trained phages demonstrated they could delay the onset of bacterial resistance.

The study, which included contributions from researchers at the University of Haifa in Israel and the University of Texas at Austin, is published June 8 in the Proceedings of the National Academy of Sciences.

"Antibiotic resistance is inherently an evolutionary problem, so this paper describes a possible new solution as we run out of antibiotic drug options," said Borin. "Using bacterial viruses that can adapt and evolve to the host bacteria that we want them to infect and kill is an old idea that is being revived. It's the idea of the enemy of our enemy is our friend."

The idea of using phages to combat bacterial infections goes back to the days prior to World War II. But as antibiotic drugs became the leading treatment for bacterial infections, phage research for therapeutic potential was largely forgotten. That mindset has changed in recent years as deadly bacteria continue to evolve to render many modern drugs ineffective.

Borin's project was designed to train specialized phage to fight bacteria before they encounter their ultimate bacterial target. The study, conducted in laboratory flasks, demonstrated classic evolutionary and adaptational mechanisms at play. The bacteria, Meyer said, predictably moved to counter the phage attack. The difference was in preparation. Phages trained for 28 days, the study showed, were able to suppress bacteria 1,000 times more effectively and three- to eight-times longer than untrained phage.

"The trained phage had already experienced ways that the bacteria would try to dodge it," said Meyer. "It had 'learned' in a genetic sense. It had already evolved mutations to help it counteract those moves that the bacteria were taking. We are using phage's own improvement algorithm, evolution by natural selection, to regain its therapeutic potential and solve the problem of bacteria evolving resistance to yet another therapy."

The researchers are now extending their findings to research how pre-trained phages perform on bacteria important in clinical settings, such as E. coli. They are also working to evaluate how well training methods work in animal models.

UC San Diego is a leader in phage research and clinical applications. In 2018 the university's School of Medicine established the Center for Innovative Phage Applications and Therapeutics, the first dedicated phage therapy center in North America.

"We have prioritized antibiotics since they were developed and now that they are becoming less and less useful people are looking back to phage to use as therapeutics," said Meyer. "More of us are looking into actually running the experiments necessary to understand the types of procedures and processes that can improve phage therapeutics."

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The study's full author list includes: Joshua Borin, Sarit Avrani, Jeffrey Barrick, Katherine Petrie and Justin Meyer.

CAPTION

Trained and untrained phages are pitted against bacteria in battleground flasks to evaluate which is more effective at killing.

CREDIT

Meyer Lab, UC San Diego

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THE CORONA VIRUS SATIRE MEME

 BIOPHAGE A GOOD VIRUS THAT KILLS SUPERBUGS

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 BIOPHAGES

Treating bladder infections with viruses

Peer-Reviewed Publication

ETH ZURICH

 

IMAGE: ELECTRON MICROGRAPH OF PHAGES view more 

CREDIT: MATTHEW DUNNE / SCOPEM / ETH ZURICH

About one in two women are affected by cystitis during her lifetime, and many suffer from recurrent urinary tract infections. Bladder infections are not only painful and potentially dangerous, but they also pose a significant dilemma for physicians. With antibiotic resistance becoming widespread in urinary tract infections and continually increasing, physicians are often forced to blindly prescribe antibiotics without knowing their effectiveness against the pathogen causing the infection. This is because it takes several days to identify a specific pathogen using conventional diagnostics.

Researchers at ETH Zurich, in collaboration with Balgrist University Hospital, have now developed a rapid test that employs the natural viral predators of bacteria, bacteriophages. The researchers also genetically modified the phages to make them more efficient at destroying the pathogenic bacteria.

Fast and reliable diagnosis

Phages are highly specialised viruses. Each species of phage infects only one particular type or strain of bacteria. ETH Zurich scientists from the Food Microbiology research group led by Professor Martin Loessner are now taking advantage of this unique characteristic. The first step was to identify the phages that are effective against the three main types of bacteria implicated in urinary tract infections, namely Escherichia coli, Klebsiella and Enterococci. These natural phages were then modified in such a way that any bacteria they recognize and infect are propelled to produce an easy-​to-measure light signal.

Using this method, the researchers were able to reliably detect the pathogenic bacteria directly from a urine sample in less than four hours. In the future, the method could make it possible to prescribe a suitable antibiotic immediately after diagnosis and thus minimize resistance development and improve antibiotic stewardship.

The method also has another advantage: it allows physicians to predict which patients are likely to respond particularly well to a tailored phage therapy, as the strength of the light signal produced in the assay already indicates how efficient the phages are in attacking the bacterium – the more the sample glows, the better the bacterium will respond to the therapy.

Double-​action sniper

Phage therapies have been used for over 100 years but fell into oblivion in Western industrialised countries with the discovery of penicillin. In view of increasing antibiotic resistance, they are currently seeing a renaissance. They also have the decisive advantage of attacking only a single target bacterium, much like a sniper.

However, previous therapeutic approaches have one problem: “Phages aren’t interested in completely killing their host, the pathogenic bacterium,” explains ETH researcher Samuel Kilcher, one of the study’s two final authors. To enhance the phages’ effectiveness, the researchers genetically modified them. The modified phages produce not only new phages inside the infected host bacterium, but also bacteriocins. Once they are released, these bacteria-​killing proteins are particularly effective against bacterial strains that have altered parts of their surface in such a way that the phages no longer recognise them. This double-​barrelled attack makes the treatment more effective.

From the laboratory to the clinic

In individual cases, such as the recent rescue of a lung patient at the University Hospital of Geneva, phage therapies have been successfully used experimentally. “There are also many academic and commercial clinical trials underway worldwide that are systematically investigating the potential of natural and genetically optimized phages,” says Matthew Dunne, one of the study's final authors. However, there is a long way to go before such therapies can be applied more widely in Western countries. In addition to extensive clinical studies, regulatory adjustments would also be useful, taking into account the fact that phages are biological entities that co-​evolve with their bacterial hosts, i.e., they are constantly evolving.

The present study is a proof of concept. Next, the ETH Zurich researchers, together with their partners from Balgrist University Hospital, will test the efficacy of the new phage therapy in a clinical trial with selected patients.

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JOURNAL

Nature Communications

DOI

10.1038/s41467-​023-39612-0 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Human tissue samples

ARTICLE TITLE

Enhancing bacteriophage therapeutics through in situ production and release of heterologous antimicrobial effectors

ARTICLE PUBLICATION DATE

20-Jul-2023

New Yale Center to Advance Phage Understanding, Treatments, Training, Education

February 14, 2022

by Julie Parry

• 
  

The Center for Phage Biology and Therapy at Yale held its launch event on Thursday, January 27, 2022, by hosting a panel discussion centered around the context of the documentary, Salt In My Soul.

Salt In My Soul chronicles the life of Mallory Smith, a woman with cystic fibrosis, by using her own words from her diary, audio and video clips that her mother Diane Shader-Smith discovered after her daughter’s passing. Smith’s doctors tried experimental phage therapy to treat a multi-antibiotic-resistant infection, but this occurred too late to prevent her death at age 25 from infectious complications after bilateral lung transplant.

Photo by Robert Lisak

Dr. Jon Koff meets with patient.

Director of the Center for Phage Biology and Therapy at Yale, Paul Turner, PhD, Rachel Carson Professor of Ecology and Evolutionary Biology, discussed the antibiotic resistance crisis and how phage therapy can combat this crisis.

The antibiotic resistance crisis is a “sobering reminder that not too far off in the future, the expected rates of death from antimicrobial resistance in the human population around the world may exceed the rates of deaths from common diseases, such as cancer,” said Turner.

“What can we do?” Turner asked. “We can harness an old technology, phage therapy, and update it for modern times. At Yale, we have had successful therapeutic use of lytic phages.”

The new Center for Phage Biology and Therapy at Yale will work to create solutions for antimicrobial resistance. Through their mission to advance and support phage research; to translate these advancements into new clinical therapies; and to train and educate students, scientists, healthcare professionals, and the community, the new Center combines the work of faculty, researchers, trainees, and staff to further develop phage for therapeutic use. These efforts bridge across Yale University and Yale School of Medicine, especially the Departments of Ecology and Evolutionary Biology and Internal Medicine.

The Center has informally existed at Yale since 2016 when a case of multi-drug resistant Pseudomonas aeruginosa was treated successfully with phage OMKO1, discovered in a water sample from Dodge Pond, a small lake in Conn.

Ella Balasa, an individual with cystic fibrosis and advocate, feels incredibly lucky to have received phage therapy at Yale in 2019. “I believe that without it [phage therapy], at this point, I would have been transplanted because of the severe lung infection that I was facing at the time,” she said.

Balasa had been struggling with antibiotic resistant infections for many years when she came across a story about Yale researchers’ work in phage therapy. She then contacted Research Scientist Benjamin Chan, PhD, scientific director of the Center for Phage Biology and Therapy at Yale. Chan started the process to obtain approval to treat Balasa via the U.S. Food & Drug Administration (FDA) investigational new drug expanded access program, or what is often called compassionate use.

“At that point, my lung function was about 20%,” Balasa said. “Phage did clear my infection. I want everyone to know that this therapy can be a viable option for antimicrobial resistance. I am excited that there are groups like you all [Yale] that are bringing clinical trials to people.”

The Center for Phage Biology and Therapy at Yale is making a multi-million-dollar investment in phage biology research and phage applications. They are currently targeting pulmonary infections in cystic fibrosis and other relevant clinical conditions. In addition, the Center will expand to address causes of sepsis, prosthetic-joint infections, post-COVID pneumonia, and other antibiotic-resistant bacterial infections in the future.

Jon Koff, MD, associate professor (Pulmonary, Critical Care, and Sleep Medicine); director, Adult Cystic Fibrosis Program; and medical director of the Center for Phage Biology and Therapy at Yale, serves as the principal investigator on the CYstic fibrosis bacterioPHage study at Yale (CYPHY), an FDA-approved human clinical phase I/II trial, developed at Yale School of Medicine and funded through Yale University, the Blavatnik Fund for Innovation at Yale, and the Cystic Fibrosis Foundation.

“[The trial] is an exemplar of using our strategy of looking more towards treating patients chronically over the long term with phages to see if we can affect their multi-drug resistant infections and see clinical improvements. It is similar to introducing an inhaled antibiotic,” explained Koff.

“The trial has been very rewarding and a great opportunity for me to engage with our patients, our community, and providers around the country. We’ve seen patients come to Yale from all over and this has allowed me to communicate to folks from multiple communities about our phage and our phage strategies,” said Koff.

In addition to Turner, Chan, Koff, and Balasa, other presenters in the one-hour virtual event were Gunnar Esiason, cystic fibrosis advocate, and graduate student at Dartmouth in the MBA/MPH program; Will Battersby, film director and producer of Salt In My Soul; and Diane Shader-Smith, Mallory Smith’s mother.

Battersby spoke about making the documentary, the themes throughout, and how people have embraced the work. “If you tell the story of somebody going through extraordinary things, extraordinary themes and lessons will emerge. I had no intention of making a film that would be picked up by the phage community in the way that it has, but it is very moving because of the possibilities in the film, […] it makes you ask so many things about phage.”

Shader-Smith shared in Battersby’s sentiment. “Mallory was willing to try phage therapy. We had many, many long talks about it. I think the main reason that people love the film, despite the tragedy, is that they leave feeling hopeful. And phage therapy is that hope,” she said.

Chan has devoted his career to furthering phage research and developing phage therapies. Despite the long history of phage usage, until recently, it hasn’t gained steam in the 0077saestern biomedical community. He gathers his strength to continue with his efforts from cystic fibrosis patients like Balasa and Esiason, parents like Shader-Smith, and supporters like Battersby.

“The cystic fibrosis community is the best. We are in it together. We help each other move through stuff. If it wasn’t for them, I would have burned out a long time ago,” he said.

Koff believes that Chan diminishes his commitment to this work. “Ben minimized his unbelievable energy to follow through on this and to have a vision for translating what he is seeing in the laboratory to the clinic. It has been an absolute pleasure working with him and seeing that level of effort,” said Koff.

“What is awesome is that I am able to be part of this process in the clinic, in the research in collaboration with Paul [Turner] and Ben [Chan] and the research group, and we can see this happening in the clinical trial context. It has been a wonderful experience for me to cross all of these aspects and I think they make our Center pretty unique,” said Koff.

The Center for Phage Biology and Therapy at Yale is funded by Yale University and philanthropic contributors who share the vision for phage therapy.

To learn more about the phage research at Yale, visit Center for Phage Biology and Therapy at Yale. For more information on the CYPHY trial, visit CYstic Fibrosis bacterioPHage Study at Yale (CYPHY). To learn more about the documentary, watch the trailer, or the film, go to Salt In My Soul.

Submitted by Julie Parry on February 13, 2022

Featured in this article

• 

  Jon Koff, MD

  Associate Professor Term; Associate Director, Fellowship Research, Pulmonary,
• Critical Care & Sleep Medicine; Director, Adult Cystic Fibrosis Program
• 

  Paul Turner, PhD

  Rachel Carson Professor of Ecology and Evolutionary Biology
• 

  Benjamin Chan

  Research Scientist

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Targeting Phage Therapy 2023: Where are we today and what's next?

Meeting Announcement

MITOCHONDRIA-MICROBIOTA TASK FORCE

 

IMAGE: THE 6TH WORLD CONGRESS ON TARGETING PHAGE THERAPY 2023 WILL BE HELD ON JUNE 1-2, IN PARIS, FRANCE. view more 

CREDIT: CREDITS TO TARGETING PHAGE THERAPY CONFERENCE

The 6th World Congress on Targeting Phage Therapy 2023 has returned to present all aspects related to phages and phage therapy on June 1-2 in Paris, France.

It will highlight the recent innovations and clinical applications of phages, validation and limitations. Paris Targeting Phage Therapy 2023 will also cover how phage will transform the medicine of tomorrow.

International phage therapy and infectious disease experts will cover the following points:

• Phage Therapy: Recent Advances & Challenges
• Bacteriophage Characterization & Isolation
• Co-Evolutionary Mechanisms of Bacteria and Phages
• Bacteriophages & Microbiota: On the Way to a Medical Revolution?
• Bacteriophage Prophylactic & Therapeutic Applications
• Phages, Radiotherapy & Wound Healing

 

Bacteriophages & Microbiota: On the Way to a Medical Revolution?

In collaboration with the International Society of Microbiota (ISM), a session will be dedicated to how phage will modulate the quality and quantity of microbiota. We will also discuss how to select the adequate phage to target microbiota dysbiosis in disease.

Session Details.

 

Paris Targeting Phage Therapy 2023 Speakers

Targeting Phage Therapy 2023 will gather a group of academic and industrial professionals worldwide to discuss their most recent research and data.

Academic Speakers:

Domenico Frezza, University of Roma Tor Vergata, Italy Phage Therapy: Vision and Gaps

Martha Clokie, University of Leicester, United Kingdom Phage Therapy & Its Applications: Where We Are Now and What’s Next?

William Summers, Yale University, USA  The History of Phage Therapy

Tristan Ferry, Hospices Civils de Lyon, France The Use of Bacteriophage Therapy for Complex Bacterial Infections: the PHAGEinLYON Experience

Anna Pistocchi, Università degli Studi di Milano, Italy Investigating the Therapeutic Potential of Phages as Antibacterials and Immunomodulators in a Zebrafish Model of Cystic Fibrosis

Rodrigo Ibarra Chavez, University of Copenhagen, Denmark Phage-inducible Chromosomal Islands Promote Genetic Variability by Blocking Phage Reproduction

Lilian Musila, U.S. Army Medical Research Directorate, Kenya Potential of Therapeutic Phages to Combat MDR ESKAPE Pathogens in Developing Nations

Jean-Paul Pirnay, Queen Astrid Military Hospital, Belgium Bacteriophages: It’s a medicine, Jim, but not as we know it

Aleksandra Petrovic Fabijan, Westmead Institute for Medical Research, Australia Therapeutic Monitoring of Phage Therapy

Noemi Poerio, University of Rome Tor Vergata, Italy A Novel Combined Host- and Pathogen-Directed Therapeutic Approach to Fight Infections by MDR- Klebsiella pneumoniae

Ryszard Międzybrodzki, Hirszfeld Institute of Immunology and Experimental Therapy PAS, Poland Phages in the Medical Research Activity in Poland

Anders S. Nilsson, Stockholm University, Sweden Novel Computer Program for Modelling Bacteriophage Infection Kinetics

Farzaneh Moghtader, Istinye University, Turkey Combined Therapies for Severely Infected Wounds: Multifunctional Bio-hybrids Composed of Gelatine Microspheres Carrying Bacteriophages and/or bFGF and their Aggregates with Mesenchymal Stem Cells

Willem-Jan Metsemakers, KU Leuven, Belgium The Use of Bacteriophage Therapy for Difficult-to-Treat Musculoskeletal Infections: the PHAGEFORCE Experience

Mzia Kutateladze, Eliava Institute of Bacteriophage, Georgia Phage Therapy: History in the Soviet Unions and Potential Treatment of Human Infections

Industrials:

Alexander Sulakvelidze, President and CEO of Intralytix, Inc., USA Modern Approaches for Optimizing Therapeutic Phage Preparations

Jessica Sacher, cofounder of Phage Directory, Australia Scaling Phage Therapy, Starting with Phage Australia

David Jernigan, PhagenCorp, LLC, USA Inducing Native Phages From the Human Virome to Address Targeted Infections

Pranav Johri, Founder of Vitalis Phage Therapy, India From Patient to Advocate – Introducing Phage Therapy to India

 

Present Your Innovations: 10 Minutes to Convince

During the Paris Targeting Phage Therapy 2023, a session will be dedicated to the latest innovations in the field of phages and phage therapy.

If you are academics, industrialists or representatives of startups, the scientific committee of Phage Therapy 2023 invites you to present your latest innovation in 10 minutes.

More information.

Tracks for abstract submission.

Abstract Submission Details.

 

Institutional Partners

This meeting is organized under the endorsement of the International Society of Microbiota (ISM).

 

Contact Us

In case you needed any further information on the registration, program, or abstract submission please visit our website.

You can also directly contact the organizing committee via email: contact@tid-site.com.

Find more information on our social media: LinkedIn and Facebook. 

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https://plawiuk.blogspot.com/search?q=PHAGES

 https://plawiuk.blogspot.com/search?q=BIOPHAGES

 https://plawiuk.blogspot.com/search?q=PHAGE

 https://plawiuk.blogspot.com/search?q=BACTERIOPHAGE