Category: Latest News

Bacteriophage Partnerships: Enhancing Stem Cell Transplant Success

Bacteriophage Partnerships: Enhancing Stem Cell Transplant Success

Posted on by Targeting Phage Therapy

Intestinal tissue during a graft-versus-host reaction: Donor cells (red) attack the body of the patient. Credit: Sebastian Jarosch, Dirk Busch / TUM

After stem cell transplantation, the donated immune cells sometimes attack the patients’ bodies. This is known as graft versus host disease or GvHD. Researchers at the Technical University of Munich (TUM) and the Universitätsklinikum Regensburg (UKR) have shown that GvHD is much less common when certain microbes are present in the gut. In the future, it may be possible to deliberately bring about this protective composition of the microbiome.

Stem cell transplantation can save the lives of patients suffering from cancers such as leukemia. However, graft versus host reactions occur following around half of these procedures. In a sense, they are the reverse of the rejection response seen after organ donations, in which the body attacks the donated organ. Here, the donated cells attack the patient’s body, for instance, in the digestive tract.It has been known for some time that microbes in the gut play a role in determining whether GvHD occurs. A team working with Dr. Erik Thiele Orberg, who heads a research group at the Clinic and Polyclinic for Internal Medicine III of TUM’s Klinikum rechts der Isar, Ernst Holler, Senior Professor of Allogenic Stem Cell Transplantation at UKR, and Prof. Hendrik Poeck, executive senior physician at UKR’s Clinic and Polyclinic for Internal Medicine, describe in the journal Nature Cancer how the gut microbiome must be composed to provide protection.
 
78 patients observed

The researchers studied stool samples from 78 patients at the two university clinics and tracked them over two years following stem cell transplantation. They used the results to develop a risk index indicating the probability of a rejection reaction. “Instead of counting bacteria, we measured the quantities of certain metabolites produced by the microbes,” says Erik Thiele Orberg.

These immuno-modulatory microbial metabolites (IMMs) influence the immune system and the body’s regenerative capacity. “It is remarkable that a positive prognosis does not depend only on IMMs from bacteria,” says Dr. Elisabeth Meedt, a physician at UKR and co-first author of the article.  “We demonstrated that certain viruses in the gut – the bacteriophages – also play a role. This alone offers an impressive insight into the complex world of our gut microbiome.”

Better prognosis with low microbiome scores

“Patients with a low IMM risk index had a higher chance of survival, showed fewer graft vs. host reactions, and experienced fewer relapses,” says Hendrik Poeck. The metabolites are formed mainly by bacteria from the families Lachnospiraceae and Oscillospiraceae in combination with the bacteriophages.

Actively improving the probability of recovery

In the next step, the researchers at TUM and UKR want to predict and actively improve patients’ chances at a cure. “By precisely controlling the composition of fecal microbiota transplants, the gut could be colonized with specific consortia of bacteria and bacteriophages,” says Hendrik Poeck. “In the coming years, we want to find out whether we can use this approach to prevent graft vs. host reactions as well as relapses,” Initial experiments with mice have been successful. As a result, the procedure could now be tested in clinical trials with human patients.

News source: Technical University Munich.

 
Rapid Bench to Bedside Therapeutic Bacteriophage Production

Rapid Bench to Bedside Therapeutic Bacteriophage Production

Posted on by Targeting Phage Therapy


An excellent paper by Luong et al. from San Diego State University has recently been published by Springer on Bacteriophage Therapy: From Lab to Clinical Practice. The comprehensive content of the paper includes:

1. Historical Context: Bacteriophages have been used in human therapeutics for over a century, with significant advancements in production techniques.

2. Modern Phage Preparations: Contemporary phage preparations are characterized by lower bacterial toxin content, reducing adverse effects and making them more suitable for therapeutic use.

3. Role in Treating MDR Infections: Due to their efficacy, therapeutic phages are increasingly being utilized for the compassionate treatment of multidrug-resistant infections.

4. Production and Ultrapurification Protocol: The article outlines a protocol for producing and ultrapurifying phages, capable of yielding over 10^9 plaque-forming units per mL for Gram-negative phages within 48 hours, compliant with FDA endotoxin limits for intravenous infusions.

5. Laboratory Requirements: The process requires a lab experienced in phage production techniques.

6. Process Illustrations and Safety Tips: Detailed illustrations and safety tips are provided to guide the removal of bacterial toxins from phage lysates.

7. Flexibility and Applications: While dependent on the phage strain, this approach is versatile and can be adapted for rapidly generating and purifying phages for various applications.

Article DOI.

Image Credits: Luong et al. Bacteriophage Therapy. Methods in Molecular Biology, vol 2734. 

How Bacteria Spot Viral Invasion and Ramp Up Immune Defenses?

How Bacteria Spot Viral Invasion and Ramp Up Immune Defenses?

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A viral RNA produced during Φ80α-vir infection activates Ssc-CdnE03 in vitro

Researchers at The Rockefeller University’s Laboratory of Bacteriology have uncovered a novel mechanism through which bacteria defend against viral infections, known as the cyclic oligonucleotide-based antiphage signaling system (CBASS). This intricate immune response protects prokaryotes by triggering the production of cyclic oligonucleotides, activating proteins that induce the death of infected host cells.

Key Findings:

  • Staphylococcal phages produce a structured RNA called CBASS-activating bacteriophage RNA (cabRNA) from terminase subunit genes.
  • CabRNA binds to the CdnE03 cyclase, promoting cGAMP synthesis and activating the CBASS immune response to prevent phage infection.
  • Phages evading CBASS defense harbor mutations leading to longer cabRNA, hindering activation and revealing insights for combating antibiotic resistance.
  • Parallels exist between CBASS and animal immune responses, highlighting shared viral sensing mechanisms across diverse life domains.
  • CBASS cyclases, central to bacterial immune responses, are considered ancient relatives of animal cyclic GMP-AMP synthase (cGAS).
  • Unlike animal cGAS sensing viral DNA, CBASS in bacteria detects specific RNA structures, identified as cabRNA during phage infection.

Future Research:

  • Ongoing investigations will delve into cabRNA’s characteristics and its role in phage infection, potentially yielding breakthroughs in understanding bacterial defense systems.

Understanding bacterial defense mechanisms, especially CBASS, holds promise in addressing antibiotic resistance. The discovery suggests using specific phages that do not trigger CBASS responses, offering a potential avenue for future research in combating antimicrobial-resistant bacteria and advancing bacterial infection treatments.

Article DOI.

Phables: Advancing Phage Research for a Healthier Future

Phables: Advancing Phage Research for a Healthier Future

Posted on by Targeting Phage Therapy

Processing workflow. Credits: Flinders Accelerator for Microbiome Exploration, College of Science and Engineering, Flinders University

In a significant leap forward for phage research, Flinders University’s College of Science and Engineering introduces “Phables”, a bioinformatics software program designed to address the challenges in identifying and characterizing phage genomes within fragmented viral metagenome assemblies. This innovative tool, inspired by the abstract’s motivation and results, marks a significant advancement in phage research.

Microbial communities profoundly influence human health and various environments, with bacteriophages or phages playing a crucial role in modulating bacterial communities. High-quality phage genome sequences are vital for advancing our understanding of phage biology, conducting comparative genomics studies, and developing phage-based diagnostic tools. However, existing viral identification tools often face challenges in viral assembly, resulting in genome fragmentation and incomplete recovery of phage genomes.

Phables tackles this issue by employing a novel computational method. It identifies phage-like components in the assembly graph, models each component as a flow network, and utilizes graph algorithms and flow decomposition techniques to identify genomic paths. Experimental results from viral metagenomic samples collected from different environments demonstrate that Phables outperforms existing tools, recovering over 49% more high-quality phage genomes on average.

Importantly, Phables has the capability to resolve variant phage genomes with over 99% average nucleotide identity—a feat that existing tools struggle to achieve. This ability to make fine distinctions contributes to a more comprehensive understanding of phage diversity and evolution.

Learn more about this fascinating tool.

Targeting Phage Therapy Team
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New Structural Antibiotic Classes Discovered through Explainable Deep Learning

New Structural Antibiotic Classes Discovered through Explainable Deep Learning

Posted on by Targeting Phage Therapy

In the relentless pursuit of novel solutions to combat the escalating antibiotic resistance crisis, a groundbreaking paper, published in the Nature Journal, reveals a pioneering approach to the discovery of new structural classes of antibiotics.

The paper challenges the current status quo in antibiotic discovery by leveraging the power of deep learning. Acknowledging the urgency of finding innovative antibiotics, the research team attempt to go beyond conventional methods and explore chemical spaces with a focus on explainability.

The prevailing issue with many deep learning models lies in their ‘black box’ nature, often lacking the ability to provide meaningful chemical insights. However, the researchers hypothesized that by identifying the chemical substructures associated with antibiotic activity, as learned by neural network models, it would be possible to predict and discover new structural classes of antibiotics.

To test this hypothesis, the team developed an explainable, substructure-based approach for the efficient, deep learning-guided exploration of chemical spaces. The study meticulously evaluated the antibiotic activities and human cell cytotoxicity profiles of an extensive set of 39,312 compounds. Employing ensembles of graph neural networks, the researchers successfully predicted antibiotic activity and cytotoxicity for an impressive 12,076,365 compounds.

What sets this approach apart is the use of explainable graph algorithms. Through these algorithms, the researchers identified substructure-based rationales for compounds exhibiting high predicted antibiotic activity and low predicted cytotoxicity. The real-world efficacy of this methodology was further validated through the empirical testing of 283 compounds.

Significantly, the study revealed that compounds demonstrating antibiotic activity against Staphylococcus aureus were enriched in putative structural classes arising from identified rationales. Of particular note, one of these structural classes exhibited selectivity against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci, demonstrated resistance evasion, and notably reduced bacterial titers in mouse models of MRSA skin and systemic thigh infection.

This breakthrough not only opens new avenues for the discovery of structural classes of antibiotics but also emphasizes the feasibility of creating explainable machine learning models in drug discovery. By providing insights into the chemical substructures underlying selective antibiotic activity, this research marks a significant step towards combating antibiotic resistance.

Contributors of this research: MIT, Harvard, Broad Institute, Integrated Biosciences, Inc., the Wyss Institute for Biologically Inspired Engineering, and the Leibniz Institute of Polymer Research in Dresden, Germany.

More information: Wong, F., Zheng, E.J., Valeri, J.A. et al. Discovery of a structural class of antibiotics with explainable deep learning. Nature (2023). https://doi.org/10.1038/s41586-023-06887-8.

Stay tuned as Targeting Phage Therapy 2024 will cover all the most recent discoveries in the field.

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Promising Path for Periprosthetic Hip Infection Recovery: The Power of Phage-Antibiotic Combination Therapy

Promising Path for Periprosthetic Hip Infection Recovery: The Power of Phage-Antibiotic Combination Therapy

Posted on by Targeting Phage Therapy

A new Russian study, published in the journal “Viruses”, study delves into the efficacy of combined phage/antibiotic therapy for treating periprosthetic joint infection (PJI) in adult patients with deep PJI of the hip joint. The research, which included 45 adult patients undergoing one-stage revision surgery, presents compelling evidence that could reshape the landscape of PJI treatment.

In this investigation, patients from a prospective study group (SG, n = 23) received treatment with a specific phage preparation and etiotropic antibiotics, while those in a retrospective comparator group (CG, n = 22) were administered antibiotics only. The results are nothing short of remarkable.

The study unveiled a staggering eightfold reduction in the rate of PJI relapses in the SG compared to the CG: an impressive 4.5% versus a concerning 36.4%, with a statistically significant p-value of 0.021. Furthermore, the response rate to treatment in the SG was an outstanding 95.5% (95% confidence interval (CI) = 0.7511–0.9976), while the CG exhibited a response rate of only 63.6% (95% CI = 0.4083–0.8198).

The odds ratio for PJI relapse in patients of the SG was a mere 0.083 (95% CI = 0.009–0.742), almost 12 times lower than that in the CG. This compelling data suggests that the combined phage/antibiotic therapy employed in the SG is a highly effective strategy in preventing PJI relapses.

This study stands as a beacon of hope, providing robust evidence that combined phage/antibiotic therapy could revolutionize the landscape of periprosthetic joint infection treatment. The implications of these findings extend beyond the realm of medical research, offering valuable insights that could shape public health policies aimed at enhancing PJI treatment protocols. Stay tuned for further developments as we continue to explore innovative avenues in the quest for improved patient outcomes.

Read the full study.

Photo credit: Depositphotos.

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Sterile Faecal Filtrate Transplantation Shows Promise in Managing Metabolic Syndrome, According to Double-Blind Clinical Trial

Sterile Faecal Filtrate Transplantation Shows Promise in Managing Metabolic Syndrome, According to Double-Blind Clinical Trial

Posted on by Targeting Phage Therapy

Overview of the faecal samples used for the bulk metagenomic sequencing (for bacteriome and phageome) and the metagenomic sequencing of the viral-like particles (VLP)

A double-blind, randomised, placebo-controlled clinical trial was conducted by a team in The Netherlands in order to assess the efficacy and safety of sterile faecal filtrate transplantation in individuals with metabolic syndrome. 

Below are the main highlights of this fascinating study:

  • Bacteriophages (phages) are known to influence microbial communities.
  • Previous research indicates that faecal virome transplantation can reduce weight gain and improve glucose tolerance in obese mice.
  •  A double-blind, randomized, placebo-controlled pilot study was conducted with 24 participants having metabolic syndrome.
  • Participants were divided into two groups: one received faecal filtrate transplantation (FFT) from a lean donor (n=12), and the other received a placebo (n=12).
  • The study’s primary focus was on changes in glucose metabolism, with secondary focuses on safety and changes in the intestinal bacteriome and phageome.
  • All participants (24) completed the study, and their data were included in the analyses.
  • No significant differences were found in glucose metabolism changes between the FFT and placebo groups.
  • The FFT was well-tolerated and there were no serious adverse events reported.
  • A notable alteration in phage virion composition was observed two days post-FFT compared to the placebo, indicating more aggressive phage-bacteria interactions.
  • The study concludes that gut phages can be safely administered to temporarily modify the gut microbiota in recipients.

You can read the full study here.

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Therapeutically useful mycobacteriophages BPs and Muddy require trehalose polyphleates

Therapeutically useful mycobacteriophages BPs and Muddy require trehalose polyphleates

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Proposed roles of Pks, PapA3, FadD23, MmpL10 and PE in the synthesis and transport of TPPs and DAT

Mycobacteriophages show promise as therapeutic agents for non-tuberculous mycobacterium infections. However, little is known about phage recognition of Mycobacterium cell surfaces or mechanisms of phage resistance.

A new study, led by Graham F. Hatfull from the University of Pittsburgh (USA) and Laurent Kremer from the Université de Montpellier (France) and published in Nature Microbiology, has shown that trehalose polyphleates (TPPs), high-molecular-weight, surface-exposed glycolipids found in some mycobacterial species, are required for the infection of Mycobacterium abscessus and Mycobacterium smegmatis by clinically useful phages BPs and Muddy.

They reported that:

  • TPP loss leads to defects in adsorption and infection and confers resistance.
  • Transposon mutagenesis show that TPP disruption is the primary mechanism for phage resistance.
  • Spontaneous phage resistance occurs through TPP loss by mutation, and some M. abscessus clinical isolates are naturally phage-insensitive due to TPP synthesis gene mutations.
  • Both BPs and Muddy become TPP-independent through single amino acid substitutions in their tail spike proteins, and M. abscessus mutants resistant to TPP-independent phages revealed additional resistance mechanisms.

Clinical use of BPs and Muddy TPP-independent mutants should preempt phage resistance caused by TPP loss.

Article DOI.

Image Credits: Wetzel et al. Nat Microbiol (2023)

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Treating bladder infections with viruses

Treating bladder infections with viruses

Posted on by Targeting Phage Therapy

The pathogens that cause urinary tract infections are becoming increasingly resistant to antibiotics. ETH Zurich researchers have now developed a rapid test and a new therapeutic approach using bacteria-​infecting viruses known as phages.

In brief
  • ETH Zurich researchers have developed a new rapid test that uses bacteriophages – viruses that infect bacteria – to quickly and accurately identify the pathogens that cause urinary tract infections.
  • This enables the targeted use of a suitable antibiotic.
  • The researchers also genetically modified the phages to make them more efficient in destroying the pathogenic bacteria.

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.

Source: ETH Zurich

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Centenarians’ Diverse Gut Virome: Potential to Modulate Metabolism and Promote Healthy Lifespan

Centenarians’ Diverse Gut Virome: Potential to Modulate Metabolism and Promote Healthy Lifespan

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After last week’s meeting Targeting Phage Therapy 2023 where Prof. Edeas talked about the role of phages in microbiota modulation, this new paper (Nature Microbiology) highlights the richness of the virome and bacteriophages in Centenarians.

Johansen et al., from Broad Institute of MIT and Harvard, presented a characterization of the centenarian gut virome using previously published metagenomes from 195 individuals from Japan and Sardinia.

The research team showed that, compared with gut viromes of younger adults (>18 yr) and older individuals (>60 yr), centenarians had a more diverse virome including previously undescribed viral genera, such as viruses associated with Clostridia. A population shift towards higher lytic activity was also observed.

They investigated phage-encoded auxiliary functions that influence bacterial physiology, which revealed an enrichment of genes supporting key steps in sulfate metabolic pathways. Phage and bacterial members of the centenarian microbiome displayed an increased potential for converting methionine to homocysteine, sulfate to sulfide and taurine to sulfide. A greater metabolic output of microbial hydrogen sulfide in centenarians may in turn support mucosal integrity and resistance to pathobionts.

These results reveal the complicated interplay between viruses, bacteria and their human hosts, and sheds light on the mechanisms by which a diverse gut ecosystem can promote health.

Article DOI.

Prof. Edeas, chairman of the Targeting Phage Therapy scientific committee, further confirms that phages will be the most strategic factor to modulate and control microbiome homeostasis.

He added: “One unanswered question is what is the exact role of prophages which are located inside bacteria to shape the microbiome? and What are the factors that activate them?”

Stay tuned about Phage Therapy 2024 to keep updated with the latest findings on phage and the microbiota.