Researchers discover rare phages that attack dormant bacteria

In nature, most bacteria live on the bare minimum. If they experience nutrient deficiency or stress, they shut down their metabolism in a controlled manner and go into a resting state. In this stand-by mode, certain metabolic processes still take place that enable the microbes to perceive their environment and react to stimuli, but growth and division are suspended.

This also protects bacteria from, say, antibiotics or from viruses that prey exclusively on bacteria. Such bacteria-infecting viruses, known as phages, are considered a possible alternative to antibiotics that are no longer (sufficiently) effective due to drug resistance. Until now, expert consensus held that phages successfully infect bacteria only when the latter are growing.

Then researchers asked themselves now whether evolution might have produced bacteriophages that specialize in dormant bacteria and could be used to target them. They began their search in 2018. Now, in a new publication in the journal Nature Communications, they show that such phages, though rare, do indeed exist.

They found them first in rotting plant material and this virus can infect and destroy dormant bacteria. This is the first phage described in the literature that has been shown to attack bacteria in a dormant state. They have named their new phage Paride.

The virus the researchers found infects Pseudomonas aeruginosa, a bacterium commonly found in many environments. Various strains colonize bodies of water, plants, the soil—and people. In the human body, certain strains can cause serious respiratory diseases such as pneumonia, which can be fatal. How the new phage takes dormant P. aeruginosa germs by surprise, however, is not yet clear to the researchers. They suspect that the virus uses a specific molecular key to awaken the bacteria, and then hijacks the cell's multiplication machinery for its own reproduction. However, the researchers have not yet been able to clarify exactly how this works.

They now aim to elucidate the genes or molecules that underlie this awakening mechanism. Based on this, they could develop substances in a test tube that take over the wake-up process. Such a substance could then be combined with a suitable antibiotic that completely eliminates the bacteria.

To test the efficacy of the Paride phage, the researchers paired it with an antibiotic called meropenem. This disrupts cell wall synthesis and so it interferes only with cellular processes that don't damage the phages. The antibiotic has no effect on dormant bacteria, as these don't synthesize a new cell wall.

When tested in cell culture dishes, the virus was able to kill 99% of all dormant bacteria but left 1% alive. Only the combination of Paride phages and meropenem was able to eradicate the bacterial culture completely, even though the latter had no detectable effect on its own.

In a further experiment  other researchers tested this combination on mice with a chronic infection. Neither the phage nor the antibiotic alone worked particularly well in the mice, but the interaction between phages and antibiotics proved to be very effective in living organisms as well.

In the case of chronic infections, that means it would be important to know the physiological state of the bacteria in question. Then the right phages, combined with antibiotics, could be used in a targeted manner. However, you need to know exactly how a phage attacks a bacterium before you can select the right phages for a particular treatment.

The researchers will now investigate precisely how the new phage brings bacteria out of deep sleep, infects them and makes them susceptible to antibiotics.

Enea Maffei et al, Phage Paride can kill dormant, antibiotic-tolerant cells of Pseudomonas aeruginosa by direct lytic replication, Nature Communications (2024). DOI: 10.1038/s41467-023-44157-3