Combination Therapy with Phage Viruses and Antibiotics Targets Antibiotic Resistance

Bacteriophage Virus attacking Bacterium
Phage about to inject a bacterium. (See my other images for pictures of coronaviruses). Modelled after an E. coli-T2-Bacteriophage or T4 Phage with all parts accurately represented: Head (containing DNA), Collar, Sheath, Tube, Baseplate with Spikes, Tail Fibres and Protein Needle.

Using ‘bacteria eating’ viruses called phages to target antibiotic resistance can be effective, but combining this approach with certain antibiotic treatments will lower the chance of resistance, suggests research from the University of Exeter.

Over the last decade much has been published about antibiotic resistance. Pathogenic bacteria and other microbes are very good at evolving and becoming resistant to drugs designed to kill them. Overuse of antibiotic drugs has exacerbated this problem and antimicrobial resistance now poses a major health problem.

Because of this, many researchers in both industry and academia are working to find novel solutions to this issue. One possibility for targeting difficult to treat bacterial infections could lie with phages. These bacteria-targeting viruses are harmless to humans and can effectively wipe out pathogenic bacteria. However, they also have some problems. Namely, bacteria can also become resistant to phages.

Edze Westra, a professor at the University of Exeter, and colleagues carried out a study to assess the best way to combat resistant bacteria using both phages and antibiotics, which is published in the journal Cell & Host Microbe.

They carried out experiments with Pseudomonas aeruginosa, a bacterial species that can cause infections in people who are immunocompromised, or have conditions such as cystic fibrosis.

The bacteria were exposed to eight different types of antibiotics and also to phage. The researchers then noted their response to both. The team found that the bacteria were able to quickly develop resistance to phage attack with some antibiotics, but not others.

Bacteria have two main ways of responding to attack by pathogens such as phage. One is by using their inbuilt CRISPR-based immune system to fight the infection and recognize and avoid it in future, a bit like a simplified version of the human immune response. The second method is for them to change their cell surface and make it harder for the virus to bind to the cell. The second response often means the bacteria become less dangerous as a result.

In this study, Westra and colleagues found that four of the eight antibiotics allowed the P. aeruginosa to develop CRISPR-based resistance to phage attack. These antibiotics were all ‘bacteriostatic’ and work by slowing growth and not killing cells.

“Antibiotic resistance is a major public health issue, and we need to take swift and urgent action. Phage therapy could be an important part of the toolkit, in reducing antibiotic use, and in using them in combination to increase their efficiency,” said Westra, in a press statement.

“We found that by changing the type of antibiotics that are used in combination with phage, we can manipulate how bacteria evolve phage resistance, increasing the chances that treatment is effective. These effects should be considered during phage-antibiotic combination therapy, given their important consequences for pathogen virulence.”

Infections such as pneumonia, tuberculosis, gonorrhoea, and salmonellosis are becoming harder and harder to treat as more resistance emerges. According to the World Health Organization, “Antibiotic resistance is one of the biggest threats to global health, food security, and development today.”

There are a number of different methods being used to overcome the resistance problems associated with more standard antibiotics. For example, other researchers are trying less direct approaches by stimulating the immune system to attack the pathogenic microbes instead of using drugs to kill them directly.

Phage therapy is one such approach. Healthcare professionals have been aware of the potential of phage therapy for a long time, but the advent and development of modern antibiotic drugs over the last 50-70 years meant it was rather ignored as a possible therapeutic option. It remains to be seen if it can prove an effective treatment for resistant pathogenic microbes, perhaps combined with antibiotic drugs, on a large scale in the future.

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