Category: Latest News

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.

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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

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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

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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?”

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Microbiome-friendly phages join the campaign for better antimicrobials

Microbiome-friendly phages join the campaign for better antimicrobials

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Phages offer a possible solution to bacterial infections that become resistant to antimicrobial agents. Credit: Stocktrek Images, Inc./Alamy Stock Photo

Biotech companies are racing to test bacteriophages — some as found in nature, others armed with CRISPR–Cas — to destroy drug-resistant bacteria selectively while keeping the microbiome intact.

Bacteriophages are attracting investor support to do the near impossible: remove harmful bacteria while leaving beneficial strains alone. Whether naturally occurring bacteriophages that infect and kill specific bacteria or ones engineered by CRISPR–Cas to target and deliver a lethal payload, what these small viruses have in common is that they do the job while leaving the rest of the microbiome intact. In February BiomX, of Ness Ziona, Israel, announced $7.5 million in funding for their phase 2 clinical trials in people with cystic fibrosis who have Pseudomonas aeruginosa infections. Armata Pharmaceuticals is also testing an inhaled phage cocktail therapy to treat P. aeruginosa associated with cystic fibrosis. In January, Armata announced $30 million convertible credit agreement to fund phase 2 trials. So far, big pharma and investors have been slow to jump in, but growing evidence to support the use of these agents, especially against the threat of multidrug-resistant bacteria, is changing that.

Phages are small viruses that infect and eliminate specific bacterial strains. Unlike antibiotics, phages are so specific they infect neither mammalian cells nor the rest of the bacteria in the microbiome. This ability to edit — rather than destroy — microbial communities is one of phages’ main assets, and scientists are enhancing their exquisitely specific killing prowess by equipping them with CRISPR-based targeted payloads.

Paris-based biotech Eligo Bioscience deploys bacteriophages that are both specific for certain bacteria and engineered to deliver CRISPR to eliminate the bacteria, an approach they call microbiome gene therapy. “When you deliver CRISPR to a bacterium, the double-stranded break caused by the CRISPR nuclease cannot be repaired and so the bacteria die,” explains Xavier Duportet, CEO and co-founder at Eligo.

In a 2014 paper, Duportet and colleagues showed that the ΦNM1 phage, which naturally infects Staphylococcus aureus, can be engineered to deliver CRISPR–Cas9 to the methicillin resistance gene. They demonstrated in preclinical tests that this phage exclusively targets methicillin-resistant Staphylococcus aureus (MRSA). The phage will “kill the bacteria that contain toxin genes, or antimicrobial resistance genes, or pro-inflammatory genes, while leaving the rest of the strains from the same species completely intact,” says Duportet.

Eligo’s most advanced antimicrobial is for treating acne vulgaris, a skin condition caused by Cutibacterium acnes. Some bacterial strains produce the pro-inflammatory peptide CAMP1 (Christie–Atkins–Munch–Petersen factor 1), which binds to Toll-like receptor 2 (TLR2) — a mediator of innate immunity in skin cells — triggering inflammation. Although antibiotics can successfully treat the condition, they also wipe out beneficial C. acnes, which have a major role in skin homeostasis. Eligo has engineered non-replicative bacteriophages to deliver an RNA-guided CRISPR–Cas nuclease designed to cut CAMP1. Eligo signed a $224 million deal with London-based GlaxoSmithKline in January 2021 that will fund preclinical research into EB005, their treatment for acne. The company has venture capital funding from Seventure and Khosla and hopes to start recruiting for human trials in moderate to severe acne in adolescents soon, with results expected in 2024.

Eligo has another bacteriophage therapy, EB003, for which it received an orphan drug designation from the FDA in October. EB003 is designed to treat severe diarrhea induced by shiga-toxin-producing Escherichia coli, a gut infection that leads to hemolytic uremic syndrome. Antibiotics do not work because killing the bacteria releases the toxin and boosts its deleterious effects. Instead, Eligo’s phage acts by targeting and eliminating the STx shiga toxin gene in the bacteria that carry it. Eligo has shown that in mice EB003 reduced colonization by shiga-toxin-producing E. coli and alleviated symptoms, according to data presented at the annual CRISPR meeting in Cambridge, Massachusetts, in 2022.

Microbiologists have until now been slow to adopt CRISPR-based tools. “One of the ironies of CRISPR is that it was invented by bacteria but has been used mainly to alter mammalian cells,” reflects Peter Turnbaugh at the University of California San Francisco, who sits on the scientific advisory board for SNIPR Biome, a Copenhagen-based company developing a CRISPR-based phage delivery system to kill harmful bacteria. In March 2019 SNIPR Biome raised $50 million in series A funding, which allowed them to start a with their live therapeutic, SNIPR001, consisting of genetically modified bacteriophages specifically targeting life-threatening E. coli. SNIPR Biome received up to $3.9 million in additional funding in May 2021 from the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X),a global non-profit funded by the US, UK and German governments, the Wellcome Trust, and the Bill and Melinda Gates Foundation for projects that target drug-resistant bacteria.

Naturally occurring phages are also making strides as antimicrobials, and their benefits are most apparent in cystic fibrosis. In people with this inherited condition, characterized by mucus build-up in the lungs and gut, P. aeruginosa forms biofilms in the lung, a major cause of morbidity. BiomX is trialing BX004, a cocktail of naturally occurring phages, to target that bacterium. Early results released in February from a study in nine people with cystic fibrosis show fewer bacterial colony-forming units after a week’s treatment with BX004 and inhaled antibiotics, compared with those in people taking only the antibiotics. Results from a phase 2 trial are expected towards the end of 2023.

Adaptive Phage Therapeutics is also in phase 1b/2 clinical trials with a phage therapy targeting P. aeruginosa in people with cystic fibrosis. The company uses an individualized susceptibility screen, testing bacteria isolated from each patient against a phage library developed at the Walter Reed Army Institute of Research and the US Navy Biological Defense Research Directorate. Adaptive Phage spun out from the navy outfit in 2016 after a patient who was critically ill with antibiotic-resistant Acinetobacter baumannii in 2016 was cured with an experimental phage inoculation. Others, such as Armata, are pursuing both natural and synthetic phages against P. aeruginosa, S. aureus and other pathogens, and a program in partnership with Merck for an undisclosed infectious disease.

Mixes of naturally occurring phages could provide a strategic advantage for treating gut dysbiosis. Eran Elinav, who co-founded BiomX, is head of the systems immunology department at the Weizmann Institute of Science and director of the microbiome and cancer division at the German Cancer Research Center (DKFZ). His team identified bacterial strains associated with inflammatory bowel disease (IBD) and the bacteriophage that can kill them, research published in Cell in August.

First, the research team identified bacteria associated with IBD, Klebsiella pneumoniae, and showed using animal models that the bacteria induce gut inflammation. Elinav’s group then hunted for naturally occurring bacteriophages that can infect and lyse the Klebsiella bacterium using the high-throughput platform developed by BiomX that screens a collection of phages against bacteria isolated from human patients. The resulting five bacteriophages were given to healthy individuals in a safety trial that is currently paused, according to a company update. BiomX also has a collaboration with German pharma Boehringer Ingelheim, based in Ingelheim, to identify microbial signatures in IBD, using metagenomics and artificial intelligence, that could be used as biomarkers for phage therapy. And both BiomX and Armata have identified phages that target S. aureus on the skin, a major human pathogen that is often antibiotic resistant, with clinical trials underway for each.

Engineered bacteriophages could also be useful for enhancing cancer treatment in situations where intratumoral microbiota contribute to tumor growth. For example, in the gut, the microorganism Fusobacterium nucleatum creates an environment conducive to tumors and is present in over 80% of tumor biopsies from patients with colorectal cancer. Rather than treat F. nucleatum with antibiotics or fecal transplants that also remove beneficial protective butyrate-producing bacteria, BiomX has engineered phage-guided treatment to suppress those specific strains by delivering genetic payloads. The company has a therapeutic consortium of phages in preclinical testing that are engineered to express a payload such as the immunostimulating cytokines GM-CSF or interleukin-15, as well as the prodrug-converting enzyme cytosine deaminase.

Similar blends of naturally occurring phages have also been deployed as food additives to target Salmonella and E. coli. In 2016 Intralytix received FDA approval for a collection of phages specific for Listeria monocytogenes. The company is embarking in collaboration with the University of Baltimore on a first-in-human phase 1/2 trial to test a collection of bacteriophages against Shigella, the bacteria that cause dysentery, as well as trials against vancomycin-resistant Enterococcus and against E. coli infection in people with Crohn’s disease.

Microbiome researchers and bacteriophage companies have a willingness and excitement to try new approaches and experiment. “The field is slowly maturing to identify therapeutic targets,” says Elinav. Companies who aim to target the microbiome “are putting forward very different-looking therapies,” says Michael Fischbach at the Departments of Bioengineering and Microbiology & Immunology at Stanford University, which shows that there is no consensus as to what approach will work. And regulatory hurdles will need to be overcome, as there are no guidelines or infrastructure for such therapeutic products to reach the clinic.

Says Fischbach, “We should expect more messiness before the cleanliness comes.”

Source: Nature Biotechnology

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Detection of Salmonella Typhi bacteriophages in surface waters as a scalable approach to environmental surveillance

Detection of Salmonella Typhi bacteriophages in surface waters as a scalable approach to environmental surveillance

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Environmental surveillance, using detection of Salmonella Typhi DNA, has emerged as a potentially useful tool to identify typhoid-endemic settings; however, it is relatively costly and requires molecular diagnostic capacity. Shrestha et al. sought to determine whether S. Typhi bacteriophages are abundant in water sources in a typhoid-endemic setting, using low-cost assays.

They collected drinking and surface water samples from urban, peri-urban and rural areas in 4 regions of Nepal. They performed a double agar overlay with S. Typhi to assess the presence of bacteriophages. They isolated and tested phages against multiple strains to assess their host range. They performed whole genome sequencing of isolated phages, and generated phylogenies using conserved genes.

S. Typhi-specific bacteriophages were detected in 54.9% of river water samples and 6.3% drinking water samples from the Kathmandu Valley and Kavrepalanchok. Water samples collected within or downstream of population-dense areas were more likely to be positive (72.6%, 193/266) than those collected upstream from population centers (5.3%, 5/95). In urban Biratnagar and rural Dolakha, where typhoid incidence is low, only 6.7% (1/15, Biratnagar) and 0% (0/16, Dolakha) samples contained phages.

All S. Typhi phages were unable to infect other Salmonella and non-Salmonella strains, nor a Vi-knockout S. Typhi strain. Representative strains from S. Typhi lineages were variably susceptible to the isolated phages. Phylogenetic analysis showed that S. Typhi phages belonged to two different viral families (Autographiviridae and Siphoviridae) and clustered in three distinct groups. 

S. Typhi bacteriophages were highly abundant in surface waters of typhoid-endemic communities but rarely detected in low typhoid burden communities. Bacteriophages recovered were specific for S. Typhi and required Vi polysaccharide for infection.

Screening small volumes of water with simple, low-cost plaque assays enables detection of S. Typhi phages and should be further evaluated as a scalable tool for typhoid environmental surveillance.

Article DOI.

In summary:

  • Typhoid phages are detectable in surface water using simple assays, in communities with high typhoid burden.

  • Bacteriophages are highly specific for S. Typhi and required Vi polysaccharide for infection.

  • S. Typhi phages have a broad lytic activity against the S. Typhi strains circulating in Nepal.

  • Phage plaque assay can be used as a low-cost tool to identify communities where typhoid is endemic.

  • The high abundance of phages in river water suggest that this could be an alternative to molecular methods for environmental surveillance for typhoid.

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Environmental Bacteriophages for Typhoid Surveillance and Evaluating Vaccine Impact

Environmental Bacteriophages for Typhoid Surveillance and Evaluating Vaccine Impact

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Typhoid-conjugate vaccines (TCVs) provide an opportunity to reduce the burden of typhoid fever, caused by Salmonella Typhi, in endemic areas. As policymakers design vaccination strategies, accurate and high-resolution data on disease burden is crucial. However, traditional blood culture-based surveillance is resource-extensive, prohibiting its large-scale and sustainable implementation. 

Salmonella Typhi is a water-borne pathogen, and here, Hooda et al. tested the potential of Typhi-specific bacteriophage surveillance in surface water bodies as a low-cost tool to identify where Salmonella Typhi circulates in the environment.

In 2021, water samples were collected and tested for the presence of Salmonella Typhi bacteriophages at two sites in Bangladesh: urban capital city, Dhaka, and a rural district, Mirzapur. Salmonella Typhi-specific bacteriophages were detected in 66 of 211 (31%) environmental samples in Dhaka, in comparison to 3 of 92 (3%) environmental samples from Mirzapur. In the same year, 4,620 blood cultures at the two largest pediatric hospitals of Dhaka yielded 215 (5%) culture-confirmed typhoid cases, and 3,788 blood cultures in the largest hospital of Mirzapur yielded 2 (0.05%) cases. 75% (52/69) of positive phage samples were collected from sewage.

All isolated phages were tested against a panel of isolates from different Salmonella Typhi genotypes circulating in Bangladesh and were found to exhibit a diverse killing spectrum, indicating diverse bacteriophages were isolated.

These results suggest an association between the presence of Typhi-specific phages in the environment and the burden of typhoid fever, and the potential of utilizing environmental phage surveillance as a low-cost tool to assist policy decisions on typhoid control.

Access full article.

Highlights of the study

  •  Typhi-specific bacteriophages can be isolated from surface waters in endemic countries using low-cost methods

  • More Typhi-specific bacteriophages are obtained in areas with higher typhoid cases

  • Typhi-specific bacteriophages exhibit diverse activity spectrum against a panel of Salmonella Typhi isolates circulating in Bangladesh

  • Environmental surveillance can be used as a tool to predict typhoid burden

 

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AP-PA02 Phage cocktail safely lowers P. aeruginosa load in Cystic Fibrosis trial

AP-PA02 Phage cocktail safely lowers P. aeruginosa load in Cystic Fibrosis trial

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AP-PA02, an experimental phage therapy for people with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa respiratory infections, was well tolerated and reduced the bacterial load in the lungs, according to top-line results from a Phase 1b/2a trial.

High doses of AP-PA02 were associated with durable reductions in bacterial load in the SWARM-Pa study.

Pharmacokinetics data, which refers to the movement of a medicine into, through, and out of the body, also showed effective delivery of the therapy to patients’ lungs with minimal exposure in other organs.

These findings support advancing AP-PA02 into a Phase 2b trial to determine its effectiveness over time, Armata Pharmaceuticals, the treatment’s developer, reported in a company press release.

Early trial in patients with chronic Pseudomonas aeruginosa infections

“We are pleased to present topline data for our lead multi-phage candidate, AP-PA02, which was evaluated in cystic fibrosis patients in the SWARM-P.a. clinical trial,” said Mina Pastagia, MD, Armata’s chief medical officer.

P. aeruginosa, a bacteria resistant to antibiotic treatment, commonly infect the lungs of CF patients, with many developing chronic infections. The bacteria also are found in people with non-cystic fibrosis bronchiectasis (NCFB), a chronic and progressive respiratory disorder characterized by airway damage.

An inhalation therapy, AP-PA02  uses viruses called bacteriophages, phages for short, that are capable of infecting and killing these bacteria. AP-PA02 is a mixture of multiple phages, an improved version of an earlier company therapy, AP-PA01, that’s designed to have a wider targeting range, greater potency, and to be capable of preventing antibiotic resistance.

The SWARM-Pa trial (NCT04596319), which ended in December 2022, enrolled 29 adults with CF and chronic P. aeruginosa infections.

Patients were randomly assigned to single or multiple ascending doses of AP-PA02 or to a placebo. Study goals were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of this cocktail phage treatment through 28 days after a last dose. Pharmacodynamics refers to a therapy’s effects on the body.

Exposure to AP-PA02, detected in patients’ sputum, increased proportionally with ascending single and multiple treatment doses, Armata reported. AP-PA02 levels also were relatively consistent among patients.

P. aeruginosa load in the sputum was measured at baseline (the study’s start) and during the trial. At its end, patients treated with AP-PA02 showed a trend toward a lower bacterial load after 10 days compared with patients given a placebo.

Those with the highest average exposure of AP-PA02 showed a sustained and marked reduction in P. aeruginosa load after treatment through to the the study’s end, with both pharmacokinetics and pharmadynamics supporting a significant effect at the highest doses. The doses used were not specified.

Pharmacokinetic “findings confirm that AP-PA02 can be effectively delivered to the lungs through nebulization with minimal systemic exposure,” the company reported.

AP-PA02 was well tolerated with a similar profile of adverse events among treated and placebo group patients. Mild and “self-limited” side effects that may be related to AP-PA02 were reported by a few patients, the release noted.

“In addition to our recently completed SWARM-P.a. study, we have line-of-sight to two additional data readouts that can potentially provide new hope to patients suffering from serious and difficult to treat bacterial infections,” said Brian Varnum, PhD, CEO of Armata.

Dosing has begun in the Tailwind study (NCT05616221) evaluating AP-PA02 in people with NCFB, the company announced. Treatment safety and effectiveness alone or in combination with inhaled antibiotics are this trial’s main goals, and results will help in designing the proposed Phase 2b study of AP-PA02 in CF patients.

“Data from Tailwind, together with our recently completed SWARM-P.a. trial, are intended to provide further evidence of the clinical value of phage therapy as a novel approach for the treatment of chronic, biofilm-related respiratory infections, and will hopefully move Armata one step closer to establishing phage as a new and powerful class of anti-infectives,” Pastagia said.

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