Research offers new hope in the fight against antibiotic-resistant bacteria

Antibiotic resistance is a serious threat to public health. When antibiotics don't work, we risk not being able to treat many types of infections and people who would previously have been cured, can die.

One example is the bacterium E. coli which is globally the most common cause of urinary tract and bloodstream infections.

What happens if a urinary tract infection cannot be treated?

Some variants of E. coli bacteria are resistant to most kinds of antibiotics. "This means that there is a very limited choice of antibiotics left that we can use. We therefore try to avoid using these "last resort" antibiotics because the bacteria can then become more and more resistant to them as well. If we use these antibiotics too often, we can end up with a situation where we have no treatment that works. An initially mild urinary tract infection can then turn into a serious threat in patients with a weak immune defence system, such as the elderly and those suffering from cancer", explains professor Ørjan Samuelsen from the University Hospital of North Norway (UNN).

Together with professor Jukka Corander at the University of Oslo (UiO) and professor Pål J. Johnsen at The Arctic University of Norway (UiT), Samuelsen has been working to find new ways of combating these antibiotic-resistant bacteria. The three professors and their team of researchers have now made a promising discovery.

Mapped DNA components in E. coli that make toxins

One of the most common ways bacteria learn to resist antibiotics is by acquiring resistance genes from other bacteria. These are often located on circular strands of the genetic material DNA (called plasmids) that are independent of the host cell's chromosome. They can therefore rapidly move between cells.

In a new study published in Nature Communications, the research team carried out a more in-depth and detailed investigation of the total genetic material of the E. coli bacteria than has ever been done before.

With the aid of the latest generation of sequencing technology, they studied the complete chromosomes and plasmids present in 2000 samples from Norwegian patients who had an invasive infection.

Plasmids develop rapidly and can spread between different strains of bacteria. We used new methods of genome analysis developed by our team for precisely this purpose, since the variation in DNA from plasmids tends to behave differently compared to the variation we see between chromosomes. We were able to study how the plasmids move around and what prevented them from moving, and this is where we made a number of promising findings. We mapped for the first time the distribution of E. coli plasmids carryingtoxin-producing genes that outcompete closely related related bacteria."

Jukka Corander, Institute of Basic Medical Sciences, University of Oslo

Tested the toxin on antibiotic-resistant E. coli

Of the twelve different toxins they found in the plasmids, there was one variant in particular that appeared to have a significant effect.

"We cultivated several types of multiresistant E. coli in petri dishes in the laboratory and added the toxin produced by the bacterial strains with a specific type of plasmid. Then we found that the toxin killed the antibiotic-resistant bacteria", says Johnsen.

This can pave the way towards new ways of treating infections, with personalized medicine as a kind of "precision-guided missile".

Findings that can reduce the use of broad-spectrum antibiotics

There is a worldwide aim to be able to reduce the use of so-called broad-spectrum antibiotics, which act against many different types of bacteria and are used when it is unclear which particular variant has infected you. The problem with such antibiotics is that they often kill too much - not only the harmful bacteria in the body, but also many useful ones.

"Broad-spectrum antibiotics usually wipe out this E. coli bacteria with toxins, which would have been nature's own weapon. We must of course treat infections, but if we instead can use personalized medicine like "precision-guided missiles" with customized antibiotics, the beneficial bacteria can survive. Our theory is that we can get bacterial strains less harmful to humans to outcompete the more dangerous variants. Then we can slow the spread of infections that are difficult to treat", explains Corander.

Corander, Johnsen and Samuelsen hope that this strategy can also work against the bacterium Klebsiella pneumoniae. They want to continue testing the toxins further.

Klebsiella can cause both pneumonia, meningitis, urinary tract infections and infections of the blood and liver. Certain antibiotic-resistant variants of Klebsiella have been classified by WHO as a serious threat to public health. In intensive care units in hospitals around the world, healthcare personnel are increasingly struggling with this bacterium.

Doctors must know which E. coli variant the patient has in order to prescribe exactly the right medicine

In order that personalized medicine can be used to combat the most harmful E. coli bacteria, the researchers must develop different precision medicines against the variants that exist.

"The diagnosis of E. coli infections must also be improved, so that doctors know which medicine to prescribe", says Samuelsen.

The study was carried out in collaboration with, amongst others, the Wellcome Sanger Institute, UiT, UNN and hospitals in different parts of Norway, and has resulted in a new, detailed overview of the variation in the total genetic material of E. coli. For instance, the researchers can see how certain genetic variants of the bacteria have developed over the last 300 years.

"This unique DNA data material will be a very important source for scientists conducting research in bacterial genetics and microbiology internationally", emphasizes Corander.

The study is funded by the Trond Mohn Research Foundation.