Study sheds light on how antibiotics and phage therapy combine to fight bacterial infections

New research has taken a step closer to harnessing viruses to fight bacterial infections, thereby reducing the threat of antibiotic resistance.

A growing number of infections, including pneumonia, tuberculosis, gonorrhea and salmonellosis, develop resistance to antibiotics, which means they become more difficult to treat, leading to higher death rates, longer hospital stays. longer and higher costs.

Phage therapy involves using viruses (called phages) that are harmless to humans to kill bacteria. Phage therapy can be used in combination with antibiotics to cure infections more effectively and reduce the risk of bacteria developing resistance to antibiotics. However, bacteria can also develop resistance to phages.

The new study from the University of Exeter, published in Microbe host cell, shed new light on how best to combine antibiotics and phage therapy. Researchers conducted laboratory experiments on Pseudomonas aeruginosa a bacteria that causes disease in immunocompromised patients with cystic fibrosis. They exposed the bacteria to eight types of antibiotics – and found differences in the mechanisms by which bacteria develop resistance to phages, which affects their harmfulness.

Viruses enter molecules on the surface of cells to infect bacteria. Like the human immune system, bacteria have their own CRISPR defense system, made up of proteins that fight infection. As in human immune responses, this means that the virus infects the bacteria and then is killed. In the process, the bacteria’s CRISPR system learns to recognize and attack the virus in the future.

However, bacteria have a second defense option. They can also modify their own cell surface to avoid infection, losing the receptor that phages normally attach to. This option comes at a cost to the bacteria – the bacteria become less virulent, which means they no longer cause disease, or the disease becomes less severe.

In the study, four of the eight antibiotics tested caused a dramatic increase in levels of CRISPR-based immunity. These antibiotics are all bacteriostatic – they do not directly kill cells but work by slowing cell growth.

Antibiotic resistance is a major public health problem, and we must take swift and urgent action. Phage therapy could be an important part of the toolkit, reducing the use of antibiotics and using them in combination to increase their effectiveness. We have found that by changing the type of antibiotics used in combination with phages, we can manipulate the way bacteria develop resistance to phages, thus increasing the chances that treatment will be effective. These effects must be taken into account during combined phage-antibiotic therapy, given their important consequences on the virulence of pathogens. “

Professor Edze Westra, University of Exeter

Phage therapy was first used in 1919, when Parisian microbiologist Félix d’Hérelle gave a 12-year-old boy a phage cocktail, apparently curing his severe dysentery. Yet despite early promises, research dried up in the 1940s as the world began to embrace the medical quick fix of antibiotics.

Today, research is gaining momentum again as part of the solution to reducing antibiotic resistance. While this is a promising alternative with some notable case studies of phage therapy in individuals, a barrier to wider use is that bacteria can rapidly develop resistance to phages, via CRISPR-Cas immunity. or by modifying their surface.

Researchers show that the effect of bacteriostatic antibiotics triggering CRISPR-Cas immunity results from slower phage replication inside the cell, which gives the CRISPR-Cas system more time to acquire immunity and eliminate the phage infection. Research therefore identifies the rate of phage replication as a crucial factor controlling the ability of CRISPR-Cas systems to defend themselves against viruses.

Lead author Dr Tatiana Dimitiru, University of Exeter, said: This study provides fundamental information on the constraints of CRISPR immune systems in the face of viruses. It was recently discovered that many CRISPR-Cas immune systems are associated with cellular responses that slow down or stop the growth of bacteria during phage infection, and we believe this may be important for cells to trigger an infection. effective immune response.

This research was funded by grants from the European Research Council under the European Union’s Horizon 2020 research and innovation program.

Source:

Journal reference:

Dimitriu, T., et al. (2021) Bacteriostatic antibiotics promote adaptive CRISPR-Cas immunity by allowing increased acquisition of spacers. Host cell and microbe. doi.org/10.1016/j.chom.2021.11.014.


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