The hospital germ Pseudomonas aeruginosa is resistant to most antibiotics. A study now shows a way to fight it with the help of other bacteria. To do this, researchers modified bacteria of the species Mycoplasma pneumoniae in such a way that they were no longer pathogenic but were able to produce proteins that attack Pseudomonas aeruginosa. In experiments with mice, the modified bacteria successfully fought the antibiotic-resistant germ.
Respiratory infections are among the top ten causes of death worldwide. A major problem is antibiotic-resistant bacteria. The bacterium Pseudomonas aeruginosa is one of the most common causes of hospital-acquired pneumonia. Among other things, it can grow on the tubes that are used in the artificial respiration of seriously ill patients. It is naturally resistant to most antibiotics and forms stable biofilms that make attacks more difficult.
bacteria as helpers
A team led by Rocco Mazzolini from the Institute for Science and Technology in Barcelona has now modified another bacterium so that it attacks Pseudomonas aeruginosa. For this, the researchers used the bacterium Mycoplasma pneumoniae, which in the wild form can also cause pneumonia. In the first step, they robbed the bacterium of its ability to cause diseases through genetic modifications and verified that mice remained healthy after contact with the modified bacterium.
“Next, we inserted two optimized genetic systems into this non-pathogenic bacterium,” the researchers report. “One that can break down biofilms and another that enables antimicrobial activity against Pseudomonas aeruginosa.” To test the extent to which the genetically optimized bacteria are actually capable of attacking biofilms of Pseudomonas aeruginosa, the researchers used breathing tubes from patients who were suffering from hospital-acquired pneumonia. They treated part of the tubes with antibiotics, part with the modified bacteria and part with a combination of both.
Activity inside and outside the body
The result: While antibiotics alone were only able to slightly reduce the colonization of the tubes with Pseudomonas aeruginosa, the living, rendered harmless bacteria significantly reduced the colonization. The most effective was the combination of modified bacteria and antibiotics. Mazzolini and his colleagues used antibiotics that target the cell wall of bacteria. Since Mycoplasma pneumoniae does not have a cell wall, this class of antibiotics cannot harm the helpful bacterium – but can attack Pseudomonas aeruginosa after the biofilm has been broken up.
Mazzolini and his team next tested the effectiveness of the “living medicine” in the lungs of a living organism in mice. To do this, they infected the animals with Pseudomonas aeruginosa, causing them to develop pneumonia. Then they treated a group of the mice with the modified bacterium; another group received no therapy. While six out of eight untreated mice died within two days, four out of eight treated animals survived for more than a week. In addition, their lungs showed less damage than those of their untreated conspecifics. Further experiments showed that the modified bacteria were also eliminated by the immune system within a few days without causing permanent damage to the lungs.
Other areas of application conceivable
“We have developed a battering ram that kills off antibiotic-resistant bacteria. The treatment creates crucial entry points for antibiotics, which penetrate the bacteria and eliminate the infections at the source,” says Mazzolini’s colleague María Lluch-Senar. “We believe this is a promising new strategy to tackle the leading cause of death in hospitals.” However, before the treatment can be tested in humans, more efficacy and safety studies are needed.
In addition to use against Pseudomonas aeruginosa, the researchers believe that other areas of application are also conceivable. “The bacterium can be modified with a variety of different payloads – be it cytokines, nanobodies or defensins,” explains Mazzolini’s colleague Luis Serrano. “The goal is to diversify the arsenal of the modified bacterium and to unlock its full potential in the treatment of a large number of complex diseases.” In this way, diseases such as lung cancer or asthma could possibly also be combated.
Quelle: Rocco Mazzolini (Barcelona Institute of Science and Technology, Spanien) et al., Nature Biotechnology, two: 10.1038/s41587-022-01584-9