🦠 A promising avenue for increasing the effectiveness of antibiotics

Aminoglycosides are antibiotics effective against a wide range of bacteria such as Escherichia coli, Pseudomonas aeruginosa or Staphylococcus aureus. But until now, no one knew how these antibiotics managed to penetrate bacteria.

Scientists from the Institut Pasteur, in collaboration with teams from Inserm, CNRS, and Université Paris Cité, have just proven that aminoglycosides use sugar transporters to cross bacterial membranes. Beyond this discovery, they succeeded in doubling the number of transporters in Escherichia coli bacteria, including the most resistant ones, thereby increasing the penetration rate and effectiveness of the antibiotics.

This fundamental discovery, which should quickly lead to clinical trials, was published on September 5, 2025, in Science Advances.


To be effective, antibiotics must necessarily penetrate inside pathogenic bacteria. Aminoglycosides, for example, efficiently manage to cross the double membrane of Escherichia coli – a Gram-negative bacterium that can cause urinary tract infections, sepsis, or endocarditis⁽¹⁾ – before blocking protein synthesis and causing its death. However, some E. coli bacteria are resistant. In 2019, the latter were responsible for 829,000 deaths worldwide⁽²⁾.

"The question of the transport mode of aminoglycosides has been the subject of much debate, one hypothesis being that antibiotics attach to the bacterial wall and cross it passively," recounts Zeynep Baharoglu, lead author of the publication and research director in the Bacterial Genome Plasticity Unit at the Institut Pasteur. But, by chance, fundamental research conducted by our team on bacterial stress in the face of antibiotics led us to a new clue."

Indeed, by studying the behavior of the bacterium Vibrio cholerae, responsible for Cholera, the researchers noticed a correlation between the effectiveness of aminoglycosides and the presence of sugar transporters – "entry gates" that specifically allow glucose, sucrose, fructose, etc., to enter the bacterium to provide it with energy. Following their intuition, the researchers therefore decided to study this transport mode in detail in Escherichia coli. And the results lived up to expectations.

"We observed, notably through fluorescence, that aminoglycosides penetrated E. coli bacteria actively, by borrowing the entry gates used by various carbohydrates. This is the first time this transport mode has been highlighted for antibiotics," rejoices Zeynep Baharoglu.

Knowing the plasticity of the transporters – whose number fluctuates depending on the type of sugar present in the environment – the scientists increased their quantity with the hope of improving bacterial permeability to antibiotics. They then tested 200 compounds, both on human biological samples contaminated by E. coli and in an animal model of urinary tract infection, which allowed them to identify a particularly effective candidate.

"It turned out that uridine⁽³⁾ allows doubling the overall quantity of sugar transporters in E. coli bacteria, resulting in multiplying their sensitivity to aminoglycosides by ten. What is also very interesting is that some resistant or even multi-resistant bacteria become permeable and sensitive to aminoglycosides again in the presence of uridine," emphasizes Zeynep Baharoglu. And similar effects are observable in many bacteria.

Hopes regarding this discovery are significant. The administration of uridine could indeed allow reducing the doses of antibiotics to be administered, decreasing the risks of creating resistance but also of potential side effects. Aminoglycosides, for example, can be toxic at high doses for the inner ear or kidneys.

"This is an important discovery that could be a game-changer for this class of antibiotics by allowing its use at lower concentration, and broadening its use to other pathologies like endocarditis or septic shock," hopes Zeynep Baharoglu.

Another perspective: "grafting" uridine to various antibiotics to help them penetrate bacteria, especially resistant bacteria.

"It's important to know that uridine is already used clinically; its lack of toxicity in humans has already been demonstrated, which will allow us to save time for synthesizing new molecules, to conduct clinical trials very quickly, and thus reduce the costs of bringing it to market," notes Didier Mazel, head of the Bacterial Genome Plasticity Unit at the Institut Pasteur. This work also shows how important it is to conduct fundamental research. Without it, this discovery, which could play a major role in the strategy to combat antibiotic resistance, would not have happened."

In 2019, according to WHO, antibiotic-resistant bacteria were involved in the death of more than 6 million people⁽⁴⁾.

Notes:
(1) serious infection of the inner lining of the heart.
(2) www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext
(3) nucleoside that contains a sugar and is a component of RNA.
(4) www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance