A new study sheds new light on how to mix antibiotics with phage therapy in the most effective way

A new study has brought us one step closer to using viruses to fight bacterial infection and so reduce the problem of antibiotic resistance.

Antibiotic resistance is emerging in a growing range of illnesses, including pneumonia, tuberculosis, gonorrhoea, and salmonellosis, making them more difficult to treat, resulting in greater death rates, longer hospital stays, and higher expenses.

Phage treatment is the concept of killing bacteria with viruses (phage) that are not harmful to people. Phage therapy can be used in conjunction with antibiotics to help cure illnesses faster and lower the risk of germs developing drug resistance. Bacteria, on the other hand, can develop resistance to phages.

A recent study published in Cell Host Microbe by the University of Exeter sheds new information on how to optimally mix antibiotics with phage therapy. Pseudomonas aeruginosa, a bacterium that causes sickness in immunocompromised and cystic fibrosis patients, was studied in the laboratory.

They subjected the germs to eight different antibiotics and discovered changes in how bacteria build resistance to phages, which affects how dangerous they are.

Viruses infect bacteria via penetrating chemicals on the cell surface. Bacteria, like humans, have their own CRISPR defense system, which is made up of proteins that fight infection. This indicates that the virus infects the bacteria and then kills it, just like in human immune responses. The bacteria’s CRISPR system learns to recognize and attack the virus in the future as a result of this process.

The bacteria, on the other hand, have a second line of defense. They can also alter their own cell surface to protect themselves from infection by removing the receptor that phages normally connect to. This approach comes at a cost to germs: the bacteria become less virulent, or the disease gets milder.

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.

Edze Westra

Four of the eight antibiotics evaluated in the study caused a significant boost in CRISPR-based immunity levels. These antibiotics are all bacteriostatic, meaning they don’t kill cells directly but instead slow down their growth.

Professor Edze Westra, of the University of Exeter, said; “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. 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.”

The first time phage treatment was utilized was in 1919, when Félix d’Hérelle, a Parisian scientist, gave a phage cocktail to a 12-year-old child, reportedly treating his acute diarrhea. Despite early promise, research ceased in the 1940s as the world began to use antibiotics as a quick medical remedy.

Now, as part of the answer to prevent antibiotic resistance, research is gaining traction once more. Although a promising alternative with some spectacular case reports of phage therapy functioning in individuals, bacteria can rapidly acquire resistance to phages, either through CRISPR-Cas immunity or by surface change.

The effect of bacteriostatic antibiotics on CRISPR-Cas immunity is due to slower phage replication inside the cell, giving the CRISPR-Cas system more time to acquire immunity and eliminate the phage infection, according to the researchers.

As a result, the speed of phage replication is identified as a critical element controlling the ability of CRISPR-Cas systems to protect against viruses, according to the findings.

Lead author Dr Tatiana Dimitiru, of the University of Exeter, said: “This study provides fundamental insight into the constraints of CRISPR immune systems in the face of viruses. It was recently discovered that many CRISPR-Cas immune systems are associated to cell responses that make bacteria slow or stop growth upon phage infection, and we speculate that this may be important for cells to trigger an effective immune response.”

The European Research Council provided funding for this study as part of the European Union’s Horizon 2020 research and innovation initiative.

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