New research has taken viruses one step closer to fighting bacterial infections, reducing the threat of antibiotic resistance.
A growing number of infections, including pneumonia, tuberculosis, gonorrhea, and salmonellosis, are developing antibiotic resistance, which means they are more difficult to treat, resulting in higher death rates, longer hospital stays, and higher costs.
Phage therapy is the concept of using viruses (known as phages), which are safe for humans, to kill bacteria. Phage therapy can be used in combination with antibiotics to cure infections more effectively and reduce the chance for bacteria to develop antibiotic resistance. However, bacteria can also develop resistance to phages.
The new study from the University of Exeter, published in Zellwirtsmikrobe, has shed new light on the optimal combination of antibiotics and phage therapy. Researchers led laboratory experiments Pseudomonas aeruginosa a bacterium that causes illness in people with compromised immune systems and cystic fibrosis. They exposed the bacterium to eight types of antibiotics – and found differences in the mechanisms by which the bacteria develop resistance to phages that affect their harmfulness.
Viruses invade molecules on the cell surface to infect bacteria. Like the human immune system, bacteria have their own CRISPR defense system, which is made up of proteins that fight off infection. As with the human immune response, this means that the virus infects the bacteria and then kills them. In the process, the bacteria’s CRISPR system learns to recognize and fight the virus in the future.
However, the bacteria have a second defense option. They can also alter their own cell surface to fight off infection and lose the receptor that phages normally attach to. There is a cost to bacteria associated with this option – 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 dramatic increases in CRISPR-based immunity. These antibiotics are all bacteriostatic – they don’t kill cells directly, but instead slow cell growth.
Antibiotic resistance is a major public health issue and we need to act quickly and urgently. Phage therapy could be an important part of the toolkit to reduce the use of antibiotics and use them in combination to increase their effectiveness. We found that by changing the type of antibiotics that are used in combination with phage, we can manipulate how bacteria develop phage resistance, which increases the chances that the treatment will be effective. These effects should be taken into account in phage-antibiotic combination therapy, as they have important consequences for pathogen virulence. “
Professor Edze Westra, University of Exeter
Phage therapy was first used in 1919 when the Parisian microbiologist Félix d’Hérelle administered a phage cocktail to a 12-year-old boy that apparently cured his severe dysentery. But despite early promises, research dried up in the 1940s when the world began to adopt the quick medical fix of antibiotics.
Now research is picking up speed again as part of the solution to reducing antibiotic resistance. While it is a promising alternative with some notable case studies of the effects of phage therapy in individuals, one obstacle to its wider application is that bacteria can quickly develop resistance to phage through CRISPR-Cas immunity or through modification of their surface.
The researchers show that the effect of bacteriostatic antibiotics that induce CRISPR-Cas immunity is due to slower phage replication within the cell, which gives the CRISPR-Cas system more time to gain immunity and clear the phage infection. Research therefore identifies the rate of phage replication as a critical factor controlling the ability of CRISPR-Cas systems to ward off viruses.
The main author Dr. Tatiana Dimitiru of the University of Exeter said, “This study provides fundamental insight into the limitations of the CRISPR immune system in the face of viruses. It has recently been discovered that many CRISPR-Cas immune systems are linked to cellular responses that slow or stop bacteria from growing when phage infected, and we speculate that this may be important for cells to trigger an 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.
Dimitriu, T., et al. (2021) Bacteriostatic antibiotics promote the adaptive immunity of CRISPR-Cas by enabling increased spacer acquisition. Zellwirt & Mikrobe. doi.org/10.1016/j.chom.2021.11.014.