Fungal infections: Cooperation of microorganisms leads to drug tolerance

Metabolisch interagierende Hefezellen. © Francis Crick Institute | Mary Wu

Berlin, 21.03.2022 – The treatment of fungal infections is often complicated by the development of tolerance to drugs. A research team from Charité – Universitätsmedizin Berlin and the Francis Crick Institute has found a cause for this in the cooperative behaviour of microorganisms. A communal relationship of different yeast cells and their interaction on the level of metabolism brings advantages for the whole community in terms of growth and survival. The mechanism now described in the journal Nature Microbiology* opens up new approaches for the development of better antimicrobial therapies.

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Fungal infections are an increasing medical problem and are more dangerous than suspected: every year, more people die worldwide from invasive – i.e. body-borne – fungal infections than from malaria. There are only three classes of drugs against such infections. However, the clinical use of these so-called antimycotics is limited by the fact that the microorganisms are often tolerant to these substances and treatment thus fails.

How does this drug tolerance develop? What role does the interaction of the microorganisms with each other play and what advantages does it bring them? A research team at the Charité and the Francis Crick Institute in London has uncovered a mechanism that links microbial metabolic cooperation and drug tolerance. “We found out that yeast cells interact actively with each other and how they exchange metabolic products in the process. In addition, we were able to show in what way this brings growth advantages and leads to tolerance to common antifungal drugs,” says the study’s last author, Prof. Dr. Markus Ralser. He is director of the Institute of Biochemistry at the Charité and heads a working group at the Francis Crick Institute. The work that has now been published is a first success of a project that has been running since 2020 to research drug tolerance in fungal infections together with Tel Aviv University, Israel, which is funded by a Synergy Grant from the European Research Council (ERC).

It is known that microbial communities are composed of both normally functioning cells and those with impaired metabolism. These metabolically deficient cells – also called auxotrophs – have lost the ability to produce some essential metabolites in the course of evolution and instead take these up from metabolically competent – so-called prototrophic – cells in their environment. What advantage this way of life brings to the cells in the community is a hitherto unsolved fundamental problem of microbiology, which the authors have now been able to partially elucidate with their study.

To investigate the co-existence of these different cell types, the research team used the power of metagenomics, which captures the totality of microorganisms in the environment: Using a huge inter-laboratory dataset comprising more than 12,000 microbial species communities from around the world, they found that communities composed of both metabolically deficient and metabolically competent cells are very common. “Such metabolically restricted, auxotrophic cells are highly prevalent, especially in collaborations associated with their host organism – and especially in the gut microbiome – and seem to enjoy an advantage,” explains Prof. Ralser, who is funded as an Einstein Professor at Charité. “We suspect that this frequent occurrence can be explained by changes in the shared metabolic environment – especially the host-provided environment with the required metabolites.”

The researchers explored the underlying biochemical mechanism using a yeast model of metabolic cooperation. This model system allowed them to separately track and study metabolically deficient and competent cell populations using state-of-the-art high-throughput protein and metabolic analysis, metabolic modelling and drug assays. By combining these technologies, they found that cooperating microorganisms with restricted metabolism, growing in community with those with functional metabolism, adapt their metabolic processes and increase the export of metabolites. In this way, they are simultaneously better able to channel a variety of antimicrobial agents out of the cell interior. 

“This mechanism thus brings advantages for both cell populations,” summarises Prof. Ralser. “On the one hand, by increasing their export activity, metabolically interacting microorganisms contribute to a rich shared metabolic environment, which the cells of the community need for growth and survival. Thus, even those with functional metabolism benefit from the cooperative relationship. Second, the drug concentration inside the cells decreases, making them more tolerant to hundreds of antimicrobials.” The findings of the study go beyond microbial ecology and open up new perspectives. Further studies should unlock the contribution of metabolism and metabolic environment to the formation of microbial tolerance and thus contribute to the development of new generations of antifungal agents in the future.

* Yu JSL et al. Microbial communities form rich extracellular metabolomes that foster metabolic interactions and promote drug tolerance. Nat Mircrobiol (2022), DOI: 10.1038/s41564-022-01072-5

Links:

Originalpublikation

ERC Synergy Projekt zur Arzneimitteltoleranz bei unbehandelbaren Pilzinfektionen (Pressemitteilung vom 5. November 2020)