His name is Paris, but he is not a hero of the Greek world but what in jargon is called “phage”, a virus that belongs to the family of those that attack bacteria. But not only that, Paride has a special characteristic, it is in fact “the first described in the literature, which has been shown to attack bacteria in a dormant state”. A young researcher, Enea Maffei, isolated the virus in Switzerland with a team from the Biozentrum of the University of Basel, under the guidance of the professor of the Federal Institute of Technology (ETH) in Zurich Alexander Harms. Paride phage-antibiotic combination therapy has demonstrated the potential to eradicate ‘hibernating’ germs both on the laboratory plate in in vitro cultures and in the murine model, in mice.
In nature, experts explain, most bacteria live with the bare minimum. If they experience nutrient deficiency or stress, they shut down their metabolism in a controlled manner and enter a resting state. In this ‘stand-by’ mode, some metabolic processes that allow the microbes to sense the environment and react to stimuli still take place, but growth and division are suspended. This also protects bacteria, for example, from antibiotics or viruses that prey exclusively on bacteria, phages, which are considered a possible alternative to those antibiotics that are no longer sufficiently effective due to the phenomenon of resistance. Until now, scientists agreed that phages successfully infect bacteria only when the latter are growing.
The researchers at ETH in Zurich, however, wondered whether evolution had produced bacteriophages specialized in dormant bacteria. And they began their research in 2018. Now, in a new publication in the journal ‘Nature Communications’, they show that these ‘mythological’ phages, although rare, really exist. A discovery born from what the authors define as a stroke of luck. When Harms and his team started the project in 2018, they were confident that within the first year they would isolate around 20 different phages that attack sleepers. But this was not the case: only in 2019 did Maffei, a PhD student at Harms, isolate a new, previously unknown virus, which they later named Paride. This virus was found in decaying plant material in a cemetery near Riehen (Canton of Basel-Stadt). The virus discovered by the researchers infects a bacterium that can be very dangerous: Pseudomonas aeruginosa. Various strains colonize waters, plants, soil, and people. In the human body, some strains can cause serious respiratory illnesses such as pneumonia, which can be fatal.
It is not yet clear to the scientists who have studied it how the Paride phage manages to take the dormant P. aeruginosa germs by surprise. They suspect that the strategy is to awaken them from their deep sleep, using a specific molecular key, and then hijack the cell’s multiplication mechanism for its own reproduction. The next step will therefore be to clarify the genes or molecules that underlie this awakening mechanism. Based on this, scientists could develop test-tube substances that take control of the awakening process. This substance could then be combined with an appropriate antibiotic that completely eliminates the bacteria. “But we’re only at the beginning. The only thing we know for sure is that we know almost nothing,” Harms points out.
In the meantime, however, the first tests show an effect. To test Paride’s firepower, researchers paired him with an antibiotic called meropenem. In vitro the virus was able to kill 99% of all dormant bacteria, but left 1% alive. Only the combination of Paride phages and meropenem managed to completely eliminate the bacterial culture. In a further experiment conducted with Nina Khanna of the University Hospital of Basel, Maffei tested this combination on mice with a chronic infection: neither the phage nor the antibiotic alone worked particularly well, but the interaction between them was proved to be very effective even in living organisms. “This shows that our discovery is not just a laboratory artifact, but could also have clinical relevance,” says Maffei.
‘Phage’ therapy has been discussed for some time. Researchers and doctors hope to one day be able to use phages to replace antibiotics that have become ineffective. However, broad applications are still lacking. “What we have at the moment are mostly individual case studies,” Harms says. Studies conducted by researchers at the Queen Astrid Military Hospital in Brussels showed that the treatment improved the conditions of three-quarters of patients and that it managed to eliminate the bacteria in 61%. However, it also means that in 4 out of 10 patients it was not possible to eliminate the germs with phage therapy. “This could be because many bacteria in the body are in a dormant state, especially in the case of chronic infections, and therefore phages cannot penetrate them,” says Harms. Hence the strategic role that those like Paride could have, even in infections with non-resistant strains.
“It would be important to know the physiological state of the bacteria in question.” And thus being able to use “the right phages, combined with antibiotics, in a targeted way. However, it is necessary to know exactly how a phage attacks a bacterium first. We still know too little” about them, explains Harms. That’s why in the coming years, researchers will study exactly how the new phage brings bacteria out of deep sleep, infects them and makes them sensitive to antibiotics.