Swedish-led team discovers potential new class of antibiotics, hope for AMR fight [Advocacy Lab Content]

A new antibiotic against gram-negative bacteria hasn’t been developed since the 1970s. Now, a European research team led by Swedish scientists has discovered multi-drug-resistant bug-killing compounds that could lead to a new class of antibiotics.

Gram-negative bacteria are a major threat to public health as they are often resistant to antibiotics. They are also the cause of many hospital-acquired infections, sometimes leaving patients in need of intensive care.

For the first time in about 50 years, a team of researchers from Sweden (Uppsala University), Denmark (Statens Serum Institut) and Latvia (Latvian Institute of Organic Synthesis) has discovered compounds that are effective against these bugs, according to a recent study published in the scientific journal PNAS.

After more than four years of testing approximately 300-400 synthesised molecules, the researchers chose two that showed potential for development.

“We identified and developed two small molecules that inhibit a protein in the lipopolysaccharide synthesis pathway in the cell wall of the gram-negative bacteria,” Anders Karlén, one of the research coordinators and a Swedish professor in computer-aided drug design at Uppsala University in Sweden, told Euractiv.

A new class of antibiotics

The two current antibiotic candidates involve attacking a new ‘target protein’. If further research and development are successful, it will signal the birth of a whole new class of antibiotics. This research work, finding new attack pathways, is often more challenging than developing new versions of existing drugs, which are more common today.

In the PNAS paper, the research team showed that the discovered molecules were effective, reducing bacteria in the bloodstream of mice to low or undetectable levels. The involved bacteria were the common multi-resistant gram-negative bacteria Escherichia coli (E.coli) and Klebsiella pneumoniae, which often cause urinary tract infections and intestinal infections. If left untreated, it could lead to sepsis, a serious condition.

These two belong to a gram-negative family of bacteria called Enterobacteriaceae, which – along with the gram-negative bacteria Pseudomonas aeruginosa and Acinetobacter baumannii– is on the WHO list of pathogens for which new antibiotics are considered to be critical – or urgently needed.

Speaking to Euractiv, Joakim Larsson, a professor in environmental pharmacology and director of the Centre for Antibiotic Resistance, CARe, at the University of Gothenburg in Sweden, says the recent discovery is a “stunning breakthrough and very good news”.

“The study is well done, and it is fascinating to see how the researchers have worked purposefully to turn the molecules into a promising antibiotic candidate despite many challenges along the way,” he explains.

Safety first

At the same time, he expressed some concern as a lot of work remains.

“Since a toxicological evaluation of the substances hasn’t been done yet, there is a risk that the candidates won’t make it all the way to a product. But let’s hope they make it, and become new antibiotics to be used in clinics. A new class of antibiotics may save millions of lives,” Larsson told Euractiv.

In the long term, however, all antibiotics developed so far have eventually been met by resistance, he explains.

“A trick bacteria have up their sleeve is that they can often exchange DNA with each other. Therefore, it may be sufficient if some harmless bacteria in the environment today carry a gene that can render the antibiotic useless, as this gene eventually may end up in those bacteria we are trying to treat,” he says.

He added: “It is therefore extremely important that we also limit the development of resistance by working on infection control and avoid unnecessary use of antibiotics.”

The next step for the Swedish-led research team will be to refine the properties of the substances found even more and make them safe for humans, said Anders Karlén.

Can take ten years

“This development process could take another four to five years. If successful, it will lead to a Phase 1 clinical trial in humans,” he says.

This means it could take up to ten years before a new product based on one of the substances discovered can be approved by the EU authorities and placed on the EU market.

The actual research project on new antibiotics is funded by the Swedish Research Council under the Enable2 platform and will run from 2022 to 2026.

Karlén said: “Currently, there are five antibiotic development projects being supported within this platform.”

The platform actually builds on an earlier European development platform Enable1, an EU project to develop novel antibiotics that ran between 2014 and 2021.

Several of the researchers behind the antibiotic study in PNAS have patented the compounds they have elaborated on and which are now also presented publicly.

[By Monica Kleja, Edited by Vasiliki Angouridi, Brian Maguire | Euractiv’s Advocacy Lab]

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