Phage therapy research brings scientists a step closer to harnessing viruses to fight antibiotic resistance

Streptococcus pneumoniae. Credit: CDC/Dr. M.S. Mitchell
Scientists are closer to harnessing viruses to treat infections as antibiotics become more resistant to bacteria.

Phage therapy refers to the use of viruses (also known as phage) instead of antibiotics to kill bacteria. An increasing number of infections such as pneumonia, tuberculosis and gonorrhoea are becoming more difficult to treat. This results in higher mortality rates, longer hospital stays, and higher costs.

Bacteriophages, or phages for short, are viruses that kill bacteria. They are a promising alternative for antibiotics and, unlike other viruses they can't harm humans. In 1919, a Parisian microbiologist Felix d'Herelle administered a phage mixture to a 12-year old boy. It apparently cured his severe dysentery. However, despite promising results, research ceased in the 40s when the world adopted antibiotics for quick medical relief. Phage research is now a part of the solution for antibiotic resistance.

Despite some impressive case studies showing phage therapy works in people, there are still many obstacles to research. One of these is recreating viruses in laboratory environments.

Experiments have been limited to exposing bacteria in a flask to phage. The bacteria interact quickly with one another and develop rapid DNA changes, which makes them resistant to phage. Any infection will persist. These flasks cannot replicate the way bacteria work in organs like the lungs. They live in "microenvironments", such as capillaries and air sacs called alveoli.

Researchers at Exeter have now developed a way to replicate these microenvironments. This allows a single bacterium to colonise one area. Instead of mixing with many bacteria, phage was introduced to each compartment in turn.

This method revealed that Escherichiacoli, a bacterium responsible for food poisonings, is not genetically resistant to the phage in these microenvironments. The majority of the bacterial population can be killed by the phage.

Dr. Stefano Pagliara is a biophysicist at the Living Systems Institute who led this research at University of Exeter. He said that "Antibiotic resistance could prove to be a more deadly killer than COVID19" if there aren't new ways to combat infection. The possibility of phage therapy is part of the solution shows great promise. Our research has helped to overcome some of these obstacles by modeling how bacteria behaves in small vessels within our bodies. It could save thousands of lives if phage therapy becomes a routine part of routine healthcare.

This research was published in PLoS Biology and is essential for the development of phage therapies that can overcome the current antimicrobial resistance crisis.

They also discovered that Escherichiacoli cells found in these microenvironments could survive treatment by phage and not develop genetic resistance. Instead, they discovered that these bacteria survived due to a lower number of phage receptors. This meant that phage had less access and these cells survived.

Professor Edze Westra from the University of Exeter was co-author. He said that "a key factor in whether phage is capable of killing bacteria is how many phage receptors it has." Higher numbers of receptors mean that phage can defeat bacteria more effectively. Our research suggests that we may be able to improve the chances of phage therapy being an alternative to antibiotics if we find ways to increase the production of phage receptors within bacteria.

This research was done in collaboration with Dstl, the Science and Technology Laboratory for Defence and Security. Dr Sarah Harding, Dstl Senior Scientist, stated that it was crucial to understand how bacteria interacts with each other in order for phage therapy to be considered as a viable treatment option. These findings will be used to create new treatments for infections caused by biodefence interests pathogens.

Published in PLOS Biology, the paper is entitled "Individual Bacteria in Structured Environments Rely on Phenotypic Resistance to Phage".

Information: Phenotypic resistance to the phage is a key factor in individual bacteria living in structured environments, PLOS Biology (2021). Information from PLoS Biology: Phenotypic resistance is a key factor in the survival of bacteria in structured environments (2021). journal.pbio.3001406