The Covid pandemic was a reminder that the development of new anti-infective agents to fight pathogenic microorganisms remains a major predicament. A recent discipline – still little known by the general public – is rising up to the challenge by studying the biology of saccharides, better known as “sugars”. “Called glycobiology, this branch of biochemistry could give rise to numerous and radical innovations,” explains Yann Guerardel, director of the Institute for Structural and Functional Glycobiology (UGSF)1, at Université de Lille, in northern France.

Glucose in the blood, starch in potatoes or wheat, cellulose in plants, exopolysaccharides in bacterial biofilms; sugars are present in all living organisms: animals, plants, micro-organisms, etc. They are some of the most abundant biological molecules on Earth. Biochemists classify them into two main groups: simple saccharides (“oses”), also called simple carbohydrates or monosaccharides that contain a single molecule (or monomer) such as glucose; and complex saccharides, also known as complex carbohydrates, made up of several oses, such as saccharose or starch. Also referred to as glycans, they are the focus of research in glycobiology.

Biology’s “dark matter”

Surprisingly, despite the omnipresence of glycans in nature, study of their biological functions remains far less advanced than that of nucleic acids (which form DNA and RNA) and proteins, which are addressed respectively by genomics and proteomics. “In analogy to the current situation in cosmology, glycans can be considered as the ‘dark matter’ of the biological universe: a major and critical component that has yet to be fully incorporated into the ‘standard model’ of biology,” emphasise the American researchers Ajit Varki and Stuart Kornfeld in a book devoted to this discipline2.

When the influenza virus enters via the respiratory tract (mouth, nose, throat, etc.), its surface proteins bind to the sialic acid on the surface of the cells, like a key in a lock.

When the influenza virus enters via the respiratory tract (mouth, nose, throat, etc.), its surface proteins bind to the sialic acid on the surface of the cells, like a key in a lock.

Centers for Disease Control and Prevention / US Department of Health & Human Services

Centers for Disease Control and Prevention / US Department of Health & Human Services

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The result is that so far in France, only three laboratories are wholly focused on glycobiology, two of which are CNRS joint units: the UGSF in Lille and the Cermav research centre on plant macromolecules in Grenoble (southeastern France). As well as playing a crucial role as an energy source, glycans are also essential to several other major biological functions: good protein folding, immune recognition or intercellular communication. Glycans are also involved in different pathological processes, such as the ability of pathogenic microorganisms to adhere to tissues, which they can prevent or, on the contrary, stimulate.

Covid infection facilitated by a sugar

For example, in order to penetrate cells in the respiratory tract (nasal fossae, throat, trachea, bronchi and bronchioles), the influenza virus binds to a sugar present on these cells: sialic acid. According to a Japanese study conducted on cells cultured in the laboratory and published in June 20223, this molecule may also be essential to the “binding” of the Covid-19 virus, SARS-CoV-2, hence the idea to try and clarify how sugars are involved in infections by different pathogens. The aim is to identify new therapeutic targets that are likely to aid in the development of new treatments that would prevent or restrict this type of adhesion and thus infections.

In Lille, Guérardel and his team are focusing on the adherent-invasive Escherichia coli bacterium (AIEC). This leads to intestinal infection and is suspected of being one of the causes of Crohn’s disease, a chronic inflammatory pathology of the gut that is characterised, amongst other symptoms, by abdominal pain and severe diarrhoea. Until recently, numerous studies had demonstrated that invasion of the gut mucosa by this bacterium can be restricted by the Saccharomyces cerevisiae yeast, or “beer yeast”. However, the precise nature of the molecules underlying this effect remained poorly understood.

In order to identify the molecules implicated, scientists isolated several major components of S. cerevisiae and evaluated their anti-adhesive and anti-infective activity against AIEC bacteria.

A discovery already patented

And they hit the jackpot! They were able to identify a complex fraction made up of glucose and mannose polymers, which not only proved able to achieve 95% inhibition of AIEC adhesion, but also drastically reduced colonisation of the mouse gut by this pathogen. “The sugars in this fraction compete with those on the surface of intestinal cells. As a result, the bacterium adheres to the former rather than the latter, which prevents infection of the cells,” explains Guérardel. Published at the end of 20214 and protected by a patent, this discovery could ultimately lead to an innovative treatment against AIEC.

E. coli bacterium binding to a lymphocyte, seen under a coloured scanning electron micrograph.

E. coli bacterium binding to a lymphocyte, seen under a coloured scanning electron micrograph.

Steve Gschmeissner / Science Photo Library

Steve Gschmeissner / Science Photo Library

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For the past twenty years in Grenoble, the team led by Anne Imberty has been concentrating on another problematic pathogenic agent, the Pseudomonas aeruginosa bacterium. This germ is responsible for severe lung infections in patients who are immunosuppressed or suffering from cystic fibrosis, a hereditary genetic disease that causes potentially fatal respiratory failure. The problem is that P. aeruginosa is resistant to current antimicrobial therapies, hence the necessity to find new drugs that are active against it. P. aeruginosa infects pulmonary cells by using two lectin proteins (LecA and LecB) to bind to sugars present on their surface, called pulmonary mucins. Thanks to X-ray crystallography, which can determine the three-dimensional structure of a given substance, the team has been able to study the structure of the molecular complexes formed by these two lectins bound to pulmonary mucins5. With a resolution close to an ångström (1 Å = 0.0000001 millimetre), they have succeeded in identifying each of the liaisons established between these proteins and the sugars.

Towards platforms to accelerate research?

These efforts have since led to the development of new molecules that could help to counteract the antibiotic resistance of P. aeruginosa. “Our work has enabled German researchers to design compounds that can bind strongly to LecA and LecB. By doing this, these products prevent the binding of these proteins to pulmonary mucins,” explains Imberty. Indeed, in articles published in 2022 and early 2023, the German team reported that it had identified two promising compounds: N‑β‑L‑Fucosylamides and the sulfonated ligand L2, which block LecA and LecB, respectively6. It is now necessary to test these compounds in humans, which should require at least another five years.

In the future, glycobiology researchers hope to see the emergence of platforms that offer a gathering point for both experts in the field and instrumentation that can analyse the sugars involved (chromatography, mass spectrometry, etc.). Guérardel is convinced that it is “an essential goal to make the analysis of glycans accessible to a broader scientific and industrial community”, in the hope that this will accelerate the development of novel anti-infective agents.

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