“Bacteria eater” with potential discovered

Certain viruses attack bacteria and could therefore be used to fight stubborn pathogens. The picture shows the promising Paride phages. © Enea Maffei / ETH Zurich

They are considered possible alternatives to antibiotics: viruses that attack bacteria. Researchers have now discovered such a virus that could have particular potential in the fight against pathogens. Because it even kills dormant germs that often escape control measures. Laboratory experiments and tests on mice showed that a combination treatment with the virus and an antibiotic can be particularly effective in eradicating such inactive germs.

Pathogens can also become sick themselves: Similar to how the coronavirus and co. affect us, special viruses target bacteria. These so-called bacteriophages dock on the surface of the single-celled organisms and then introduce their genetic blueprint and other programs into the victim. This forces the bacterium to produce many more virus particles. Ultimately, this infection causes the bacterial cell to die by rupturing and releasing the viral pathogens. They then go looking for more victims. Scientists have been working for some time to turn these enemies of bacteria into our allies: as weapons against bacterial pathogens, they could represent an alternative to antibiotics, which are increasingly losing their effectiveness due to the development of resistance.

Problematic slumber state

Such phage therapies have already achieved initial success, but further research appears to be necessary to exploit their potential. The scientists led by Enea Maffei from the University of Basel have now looked at an aspect that is also a problem when using antibiotics: Both methods are effective against active bacteria - however, dormant germs can survive treatments unscathed and become a source of infection again. To explain: When bacteria are in a resting state, their metabolism is still running on a low flame, but growth and division are at a standstill. However, it is precisely in these processes that the effects of many antibiotics come into play, and bacteriophages also seemed to be dependent on the attack of active bacteria. But Maffei and his colleagues wondered whether, given the countless types of phages, there might not be some that specialize in infecting dormant bacteria.

After a long search, the researchers actually found what they were looking for: They isolated a previously unknown virus from rotting plant material that met the search criterion. Experiments with dormant bacteria showed that the pathogen can also infect and destroy these otherwise stubborn germs. What was special was that the virus, known as Paride, can crack a particularly notorious bacterial species in its dormant state: Pseudomonas aeruginosa. Different strains of this microbe colonize water, plants and soil. However, certain versions can also cause life-threatening respiratory diseases such as pneumonia in humans. Experiments in culture dishes showed that the virus was able to kill 99 percent of all dormant Pseudomonas aeruginosa bacteria. Further research must now clarify how exactly the pathogen manages to do this. But the scientists assume that the virus forces the infected cells to wake up using a molecular mechanism. This allows it to exploit the reproduction machinery of the hijacked cells to multiply - until they finally collapse.

Promising test results

In order to catch the one percent of bacteria that the phages apparently couldn't kill, the researchers added the antibiotic meropenem to the culture medium. Normally it has no effect against dormant bacteria because it only attacks cell wall synthesis in growing bacteria. However, the combination of paride phage and meropenem wiped out the entire bacterial culture. The team attributes this to the activating effect of the phage, which, in combination with the antibiotic, led to the complete knockout blow.

After this success, the researchers moved on to animal experiments - they tested the treatment concept on mice with a chronic infection. This showed that the phages or the antibiotic did not work particularly well on their own. But the interaction also proved to be extremely effective in the fight against infections in living organisms. “This allowed us to show that our discovery is not just a laboratory artifact, but could also be clinically relevant,” says Maffei.

Perhaps in the future, a phage-antibiotic combination treatment could effectively combat chronic infections in which many of the pathogens may be in a dormant state. Above all, the team now wants to devote itself to elucidating the mechanism by which the phage appears to awaken the bacteria. There could be far-reaching potential in the corresponding genes and molecules: Based on this, substances could be developed that can wake up stubborn, slumbering bacteria. Such an active ingredient could then be combined with a suitable antibiotic that alone does not completely eliminate the bacteria. “But we are only at the beginning,” concludes senior author Alexander Harms from the University of Basel.

Source: Swiss Federal Institute of Technology Zurich, specialist article: Nature Communications, doi: 10.1038/s41467-023-44157-3

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