“Pseudomonas aeruginosa is an unwelcome guest,” says Steven Hagens of the Institute of Food Science and Nutrition. In fact this bacterium is still the cause of serious illnesses in humans, such as pneumonias, infections of burns or stubbornly resistant hospital-acquired infections. A particularly disagreeable aspect: antibiotics are scarcely able to harm this bacterium any longer because Pseudomonas aeruginosa has pump mechanisms that rapidly expel antibiotics back into the environment from the cell’s interior. There are also strains that have developed resistance to what were once medicine’s miracle cures.

Astonishing discovery by chance

However, as a by-product of the dissertation that Hagens wrote at Vienna University, he has now discovered something which raises hopes in the battle against Pseudomonas. He says modestly that “It was purely fortuitous and had nothing to do with my actual topic.” (1) What Hagens really found was that certain strains of Pseudomonas aeruginosa can be checked if they are fought not only with the customary antibiotics but also by using certain filiform (filamentous) bacteriophages at the same time. In principle phages are viruses that can infect and kill bacteria. However, the filamentous phages that Hagens used do not kill their host, they only parasitize Gram-negative bacteria. Pseudomonas is one of these Gram-negative bacteria.

The cell wall becomes more permeable

His experiments allowed him to show that Pf3 and Pf1 phages can successfully insert their gene into Pseudomonas. These DNA sequences code for membrane proteins that ultimately – as the researcher suspects – create channels in the bacterium’s cell wall. It is possible that antibiotics are able to enter the cell through these gateways more quickly than it can dispose of them. Nonetheless this mechanism remains only a hypothesis, although a few studies point in that direction. “I did not have enough time to find out everything we need to know,” says Hagens with regret. As a postdoc at ETH he continued the work begun in Vienna but did not find answers to all the outstanding questions.

Combination therapy works in mice

However, he did demonstrate by tests in mice that a combination therapy using the antibiotic Gentamicin and the phages is effective. Animals infected with a lethal dose of the bacterium recovered when both the antibiotic and the filamentous phages were administered to them.

A filamentous phage under the electron microscope (Photo: Biomedicine Research and Study Center, Riga)

However, the inflammation was not cured if they received only one or the other of the two treatments. Even a strain of P. aeruginosa containing a gene for resistance to Gentamicin became vulnerable to this antibiotic again thanks to the phages.

Hagens’ discovery is significant because bacteria have developed resistance to many of the usual antibiotics. This increasingly blunts these medicines as a weapon against infections. Although bacteriophages may not replace conventional treatment, they might be an appropriate complement to it. Combination therapy using phages could then make progress when a bacterial strain was susceptible to a particular filamentous phage. His comment is: “We live at a time when we must explore every possibility.”

Finding matching phages

First of all it is necessary to isolate and characterize a pathogen in order to discover whether there is any possibility at all of a matching phage to fight it. Hagens assesses the risk that bacteria will adapt to their enemy as rather small. This is because bacteriophages recognise structures on the host that the latter cannot alter very quickly because they are vital to its survival. For example a bacterium could modify a surface protein onto which the phage docks. But Hagens suspects that “this might weaken the bacterium.” In addition the phages in their turn will also adapt to changes again and again.

It is uncertain whether Hagens’ chance discovery will result in a therapy for humans. Only one company has expressed an interest in it, and they remained uncommitted. The researcher himself was not able to follow the trail any further. He will leave ETH, and although the company that he will join does work with phages, it uses them in the foodstuffs industry. This is also the direction in which ETH Professor Martin Loessner’s research is aimed. Among other thinks, his group will investigate whether phages can be used against the dangerous Listeria that occur in soft cheeses such as Vacherin. (2)