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Phage therapy: Using predator viruses to destroy multidrug resistant bacteria

Phages attack and infect host bacteria

The number of patients killed by multiple drug resistant (MDR) bacteria is rising every year as antibiotics are losing their effectiveness. Phages – which were used before the advent of antibiotics and then forgotten in the Western world for almost a century – are rapidly becoming one of the most promising alternatives to antibiotics.

Antibiotic resistance is a serious and growing threat to global health, as more and more infections are becoming harder to treat. In a 2018 study by the European Centre for Disease Prevention and Control (ECDC), based on data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) from 2015, it was estimated that about 33,000 people die anually as a direct consequence of infection with antibiotic-resistant bacteria.1 The US Centers for Disease Control and Prevention (CDC) reports similar figures, with 2.8 million infected patients and more than 35,000 deaths anually in the United States 2. According to Keiji Fukuda, former Assistant Director-General of the World Health Organisation (WHO), ”We are losing the ability to treat infections. By 2050, estimates indicate more people could die from antibiotic resistant infections than those who currently from cancer.”3

In their search for alternatives, scientists are rediscovering a hungry predator with an appetite for bacteria. Bacteriophages, commonly shortened to phages (from the ancient Greek, meaning “to eat or devour”), are viruses that infect bacteria 4. They inject their DNA inside their host and replicate inside, using the bacteria’s own metabolic mechanisms, until the bacteria explode, releasing new phages. Their anatomy makes this possible: Bacteriophages have a ‘head’, which contains the genetic material enclosed in a protein envelope, and a fine protein ‘tail,’ with the receptor for binding to the bacterial cell surface. The structure of this receptor is so specific that a phage can only attack bacteria having a cell surface that exactly “matches.”5 Therefore, phages target only a specific bacterial host without damaging human cells or other bacteria. In fact, phages are everywhere in our environment, and their numbers exceed the populations of any other biological entity on earth.

Characterising phages with modern sequencing technologies

Roughly a century ago, researchers began testing the use of phages to control certain bacterial infections. However, phage therapy was quickly dismissed in Europe and in the United States after the discovery of antibiotics, and their therapeutic potential remained unexplored in Western countries. Doctors in Russia and Eastern Europe, however, continued to use them successfully to treat wound infections and diseases such as gastroenteritis and sepsis.

Since the early 21st century, researchers have used new sequencing technologies to better characterise, and even to modify the genome of phages. Phage engineering has allowed to quickly create phage variants with unique properties, making them a highly specific weapon against bacterial infections 6. In the past decade, phage-based therapy has experienced a renaissance, often as a last resort for patients with MDR infections in Western countries. Encouraged by individual cases of therapeutic success, researchers have initiated larger clinical studies to assess whether phage therapy could become an effective alternative or complement to antibiotic treatment. Scientific institutions are also expanding their libraries of characterised phages in order to be able to quickly offer suitable phages for specific bacteria.

Reintroducing phage therapy in Germany

The publicly funded project Phage4Cure7 is the first study in Germany to use purified phages as inhalation therapy against Pseudomonas aeruginosa, the most common cause of pneumonia in patients with cystic fibrosis. The participating organisations aim to develop a completely new therapy, starting with the selection of promising phages through the production of a pharmaceutical-grade therapeutic agent, and all the way to its testing in preclinical and clinical studies. “Our goal is to develop phage-based therapy as an alternative for treating certain infectious diseases – particularly in cases where antibiotic treatment has failed,” explains Prof Holger Ziehr, project leader at the Fraunhofer ITEM.8

Such projects are important first steps toward making phage therapy available for patients with MDR infections. Scientists will still need to clear a number of hurdles, however. The costs of producing good manufacturing practice (GMP) phage therapeutics are high, and researchers have not yet fully characterised phage biology, nor do they fully understand how phages interact with pathogenic bacteria.9 Yet developing phage-based therapies are worth the effort, as these bacteria-killing viruses could become valuable allies in the fight against antibiotic resistance.

FURTHER INFORMATION

  1. 33000 people die every year due to infections with antibiotic-resistant bacteria, European Centre for Disease Prevention and Control
  2. Antibiotic/ Antimicrobial Resistance, Centers for Disease Control and Prevention
  3. Ahead of major health meeting, senior UN official sheds light on growing threat of antibiotic resistance, United Nations
  4. Understanding and Exploiting Phage–Host Interactions, Edel Stone et al., Viruses — Open Access Journal
  5. What are bacteriophages, Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures
  6. Genetic Engineering of Bacteriophages Against Infectious Diseases, Yibao Chen et al., Frontiers in Microbiology
  7. https://phage4cure.de/de/
  8. Neue Wirkstoffe gegen multiresistente Keime, Britta Widmann, Fraunhofer Gesellschaft
  9. Phage therapy’s latest makeover, Charles Schmidt, Nature Biotechnology
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