Slimy weapons against fungal infections

The fungus Candida albicans in its harmless spherical form (left) and its dangerous filamentous version (right). © Julie Takagi/Daniel Mathys

Hope in the fight against the notorious candidiasis: Researchers have identified substances in mucous membrane secretions that can keep the fungus Candida albicans in check. The special representatives of the so-called glycans suppress the development of the normally harmless mucosal inhabitant into its harmful form. The scientists have also succeeded in artificially producing the active slime components. This could lead to the development of a new class of drugs that put the stubborn pathogens in their place in a comparatively natural way.

The human body is home to a motley community of microbes that do not normally cause any problems or are even important to our health. However, the microbiome also includes potential bad guys—bacteria or fungi that can cause harm when out of control. One such tricky representative is the yeast Candida albicans, which is found on the mucous membranes of most people. In its spherical form it is unproblematic. But under certain circumstances, the fungus begins to form invasive networks. Through this so-called filamentation, Candida can cause diseases such as oral thrush, vaginal yeast infections or even life-threatening systemic infections. Then only the chemical club can help – but there are only a few effective antimycotics and they have problematic side effects. Alternative treatment options are therefore in demand.

On the trail of slime effects

An international team led by Rachel Hevey from the University of Basel and Katharina Ribbeck from the Massachusetts Institute of Technology in Cambridge is currently looking for substances with an antifungal effect. The researchers’ approach is to make substances of our natural defense system usable. In the case of the mucous membranes, their characteristic feature plays a central role: the secretion. Studies over the past few years have shown that mucus offers not only physical protection, but also pharmacological ones. There were already indications that there are active substances in the mucus that counteract the problematic development of Candida. However, it remained unclear which components are exactly responsible for this effect.

As part of their study, the researchers focused on a group of special sugar molecules in human mucus that have already been shown to have effects against certain pathogens. These so-called glycans are a main component of the mucins, which in turn are responsible for the gel-like consistency of the mucus. First, the scientists made it clear through experiments with mucus samples that the secretions can actually suppress the filament formation of Candida albicans. They then analyzed the molecular composition of the active mucus samples. They identified over a hundred different glycans with potential antimicrobial activity.

potential for medicine

From the representatives that were most common in all samples, the team then synthesized six candidates for further analysis. “It is almost impossible to isolate glycans from mucus samples,” explains Hevey. “Therefore, the only way to study their properties in more detail is to synthesize them. However, this is an extremely complex chemical process”. However, with the help of a specially developed method for synthesizing these molecules, the team finally succeeded in artificially replicating the glycans and producing them in usable quantities. The scientists were then able to use these substances to carry out tests on cultures of Candida albicans in the laboratory.

This confirmed that the synthesized glycans were able to suppress the filamentation of the yeast fungus, i.e. the change from the harmless to the infectious form. According to the scientists, their ongoing work on other bacterial and fungal pathogens also shows that these polysaccharides have considerable medical potential. They could thus become the basis for the development of a new class of drugs. “It becomes clear that mucus contains an extensive library of small molecules with many virulence inhibitors against all sorts of problematic pathogens just waiting to be discovered and exploited,” says Ribbeck.

The development of drugs against fungal infections is of particular importance, emphasizes Hevey: “There is an urgent need for new antimycotics. For a long time it was thought that glycans were only responsible for the sliminess of the mucus. Now we see that they could actually pave the way for new, much-needed drugs against these problematic pathogens.” The researchers will continue to work towards this goal. Among other things, they are currently looking for ways to bring the glycans to different areas in the body.

Source: University of Basel, specialist article: Nature Chemical Biology, doi: 10.1038/s41589-022-01035-1

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