Phage Therapy is starting to realize its long-deferred potential

Phage Therapy is starting to realize its long-deferred potential ...

Katarina Zimmer, author of Katarina Zimmer, speaks out.

Soon after Frederick Twort's 1915 study, tiny microbes were shown to be therapeutic potential. Twort suggested that bacteria-depleted zones on his culture plates might have been caused by an ultra-microscopic virus, but he cautiously permitted that they might have been caused by a strictly bacterial process. dHerelle was more bold. He quickly focused on what he called the bacteria bacteriophagethe eater.

In 1919, dHerelle and his colleagues administered a cocktail of different phages to a 12-year-old boy with dysentery, who reportedly recovered within days. Early successes such as these prompted interest in the development of phage therapyat least until the advent of broad-spectrum antibiotics. Antibiotics rapidly developed, thus interest in using viruses to treat bacterial infections quickly waned in the United States and Western Europe.

phages are now in the limelight in Western medicine as the worrying spread of antibiotic resistance among bacteria has underscored the need for new antibiotic-killing therapies. Drug-resistant diseases cause around 700,000 or more deaths annually, bringing the total number of deaths to 10 million annually by 2050, according to one of the figures cited by the United Nations Interagency Coordination Group on Antimicrobial Resistance.

The dangers of antimicrobial resistance are complex and complex, according to a research, but they are not unsurmountable. Despite this, phage therapy experts are widely aware that viruses may encounter antimicrobial resistance, and that they are often too specific to be broad effective. Nonetheless, many phage therapy experts are optimistic about progress.

At the fourth annual Bacteriophage Therapy Summit (a digital event that took place February 1416, 2022), phage therapy specialists discussed new insights into phage-bacteria interactions, the capabilities of new development platforms, and novel strategies to eradicate drug-resistant or otherwise problematic bacteria. On the whole, participants maintained that phages are poised to become effective therapeutics.

Infections can be traced into complex matrix-reinforced biofilms on implant surfaces, protecting themselves from the host immune system and antimicrobial therapy, according to Hesham Abdelbary, an orthopedic surgeon at the Ottawa Hospital in Canada.

At the meeting, Abdelbary stressed that biofilm formation is a terrible process. He suggested that it be avoided by lytic bacteriophages. These microbes produce enzymes that break down biofilm matrices and kill the bacterial cells inside.

In one 2018 in vitro study, Abdelbary and his colleagues found that administering the Staphylococcus aureustargeting phage SATA-8505 prior to certain antibiotics would kill the biofilm-forming bacteria much more effectively than either treatment alone.2, I see phage therapy as a supplement to antibiotics. It's not a replacement.

Molecular biology team from Universite Laval and Cytophage Technologies are working to determine an antibiotic-enhancing cocktail of different phages, a technique that decreases the likelihood of bacteria tolerating the therapy if they develop resistance to individual phages.3 The next step is to investigate the efficacy of phages in infected rats via local injections or implant coatings.

Vesale Bioscience, a Belgian biotechnology company, is pursuing a personalized phage therapy approach. To Bob Blasdel, the company's research director, the limited use of phage cocktails in previous clinical trials illustrates the difficulties in implementing a one-size-fits-all therapeutic that works across a broad spectrum of bacteria in different patients.4 Moreover, Blasdel believes that the current approach of testing and approval of fixed antimicrobial therapies is unsustainable.

At the presentation, Blasdel supported this view by pointing out that bacteria enhance resistance faster than new drugs can be developed. He added, we recognize the need for a model that can deal with bacteria that affect patients.

The company's goal is to provide physicians with a phagogram to quickly identify the most effective phages for a given patient. The diagnostic tool includes a panel that includes up to 15 phages that can be tested against Staphylococcus, Pseudomonas, and Klebsiella isolates; new phages may be added if bacterial resistance arises.

The phagogram is designed to detect ATP released by dying bacteria and shows that the phages outreplicate the bacteria. Pharmacists may then tailor personalized medicines based on the two or three winning phagesan strategy that has been used on more than 100 patients with various infections at Belgium's Queen Astrid Military Hospital.5

This approach might be commercialized through an extrapolation of Belgium's magistral preparation framework and a set of regulations for compounding/pharmacy preparations. It is designed to allow pharmacists to prepare personalized therapeutics in instances where conventional therapies such as antibiotics arent sufficiently effective or safe for certain patients, for example, due to antibiotic resistance or medication allergies. It is a way to avoid the need for clinical trials for each phage formulation.

Magistral preparations can shift the focus of evaluations from treatments to diagnostics. It's the diagnostic that we'll be testing for safety and efficacy, according to Blasdel.

Other groups are tinkering with the DNA of bacteriophages to make them more effective killers. For example, Phico Therapeutics, a biotechnology organization in the United Kingdom, is rapidly developing phages to develop a gene for a small, acid-soluble spore protein (SASP) into bacterial cells.

SASPs are usually expressed during sporulation, when SASPs are used to coat and protect the DNA of bacterial spores. However, when SASP genes are sent to normal-growing bacteria, the bacteria express SASPs that link to and activate their own DNA. This immediately stops gene transcription, according to Heather Fairhead, PhD, and Phicos CEO. The replication of bacteria, however, is usually stopped.

Because SASPs bind to DNA in a sequence-independent manner, they will silence bacterial genomes even if bacteria mutate in ways that strengthen resistance to bacteria. At Fairhead, the technology used in Phicos is based either on individual phages or mixtures of closely related phages, which are genetically modified to broaden the range of bacterial strains they infectan approach.

SASPs still kill 225 diverse isolates of Staphylococcus aureus due to in vitro experiments by Phico scientists. Many of them were resistant to antibiotic methicillin or an ancestral wild-type phage.6 Even in bacteria that are resistant to the phage internallyso they can degrade the phage DNAwe still have been slaughtered by SASPs, according to Fairhead.

The aim of the Phase I study is to develop PT1.2 as a gel for certain surgery patients to decolonize methicillin-resistant bacteria in the nose to prevent subsequent wound infection. However, Phicos is still developing an intravenous phage therapy for ventilator-associated pneumonia caused by drug-resistant Pseudomonas aeruginosa. Phase I research is scheduled for 2023.

Felix Biotechnology, a California-based company, has developed phages to broaden the range of bacterial strains that can be identified. These algorithms, for example, are then used to identify genetic signatures associated with a phage's host range. We primarily employ this technology to characterize a phenotype, according to Robert McBride, the company's co-founder and CEO.

Felixs primary focus is on developing therapies for patients with life-threatening infections. In 2021, the company began a Phase I/ II experiment to determine the inhalable phage therapy YPT-01, which includes phages selected for various advantages, including ones that aim to regenerate bacteria to antibioticsin 36 cystic fibrosis patients.7 The study used wild-type phages, but the commercial version of YPT-01 is not altered, according to McBride.

Felixs scientists are collaborating with skin care firms to develop chemical-free methods to treat harmful bacteria such as bed sores and diaper rashes. phages are really well-positioned to be like precision bombs, according to McBride. [They can] go in there and remove the bad bacteria and preserve the good bacteria.

The Felix grenades promise to outperform traditional phage cocktails that may work well in situations where only one dose is required, such as pneumonia, but may also falter in situations where repeated doses are required. However, Felix's precision snipers may be a more effective technique in situations where repeated bacterial outbreaks occur.

Locus Biosciences, a North Carolina corporation, is specialized in modifying phages to produce a CRISPR genetic modification system. Rather than the popular DNA-snipping Cas9 enzyme, the phage DNA encodes a Cas3 system, which effectively shreds and destroys bacteria DNA, according to Paul Garofolo, the company's co-founder and CEO.

The goal of each infection event is to make every infection event a kill event, according to Garofolo. LBP-EC01, a cocktail of six CRISPR-Cas3-harboring phages designed to combat multidrug-resistant Escherichia coli strains in urinary tract infections, is now being tested in a Phase II/III model.

phages are also experimenting with other methods, such as inducing resident gut bacteria to express therapeutic molecules. If phages could be employed this way, they might avoid one of the limitations of conventional therapy for ulcerative colitis or Crohns disease. While conventional therapies are systemically delivered through the bloodstream, they tend to build up in the liver and kidneys without reaching high enough concentrations in the gut itself.

Locus scientists are tinkering with phages that are developed to encode molecules such as interleukin-10 or tumor necrosis factor-alpha inhibitors, which may be ingested orally and thus shipped to the gut, where they infect certain bacteria and induce local production of the molecules. This is where the goal of the researchers to understand why it is important to seek out a far greater therapeutic impact.

The applications for phage technology range from the killing of bacteria to the modulation of the human microbiome. Garofolo says the limitations are unknown.

As we learn to optimize a patient microbiome to treat disease, I think we will develop a brand-new field of medicine in the next 20 years.

Viruses 2019: 127. DOI: 10.3390/v10101038. 4.Cass J, Ibrahim M, and De Vos D, respectively, et al. A randomised, controlled, double-blind phase 1/2 study for Pseudomonas aureus biofilms. Lancet Infect. 2018; 10: 355. DOI: 10.3390/v10101038. 7.Cass J, Ibrahim M, Taha M, and

Katarina Zimmer, a self-employed science and environmental journalist, is a contributing author for GEN.

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