Yeast Collaborate to Develop Drug Tolerance

Researchers in Germany and United Kingdom have uncovered a mechanism that links metabolic interactions between yeast cells in communities with tolerance to antimyotic antifungal drugs. This collaboration, which they describe in a recent issue of Nature Microbiology, presents new opportunities for developing treatments to the growing issue of fungal diseases.

Comprised of researchers from Charité in Berlin and the Francis Crick Institute in London, the team set out to discover why clinical use of antimycotic drugs—of which there are only three classes—is increasingly hampered by drug tolerance. “We discovered that yeast cells frequently and actively engage with one another, and that these interactions involve the exchange of metabolites,” says  Prof. Dr. Markus Ralser, Director of Charité’s Institute of Biochemistry and Group Leader at the Francis Crick Institute. “We were also able to show how this creates both growth advantages and tolerance to common antimycotics.”

This metabolic engagement between cells benefits the entire community, both in terms of its growth and survival. Cells with impaired metabolism, also known as auxotrophic cells, have lost the ability to produce certain essential metabolites but can instead absorb them from metabolically competent, or prototrophic, cells within the community. The question of whether, and to what extent, cells in this community benefit from this communal existence had previously remained one of the key unsolved problems in the field of microbiology. 

In order to study the coexistence of these different cell types, the researchers analyzed the genetic makeup of all microbial communities present within the environment. Using a data set collated from numerous laboratories and comprising data on more than 12,000 microbial species communities from across the globe, the they found that communities with both auxotrophic and prototrophic cells are extremely common.

“These metabolically deficient (auxotrophic) cells are particularly common in host-linked cooperative communities—especially in the gut microbiome—where they appear to enjoy an advantage,” says Ralser. “We suspect that their ubiquity can be explained by changes in their shared metabolic environment, particularly the environment provided by the host which features the required metabolites.”

The team then used a yeast model of metabolic cooperation that enabled them to observe populations of metabolically deficient and metabolically competent cells in isolation. They then analyzed these cell populations using high-throughput proteomics and metabolomics technologies, metabolic modeling, and drug susceptibility testing. They found that, due to metabolic adaptations necessary to uptake specific metabolites, auxotrophic yeast living in cooperative communities end up favoring the export of other metabolites. This increased efflux activity reduces intracellular drug concentrations, allowing cells to grow in the presence of drug levels above minimal inhibitory concentrations

“This mechanism has benefits for both cell populations,” Ralser says. “By increasing their export activity, metabolically interactive microorganisms help to create a common environment which is rich in metabolites, and which the community’s cells need for their growth and survival. This means that even metabolically competent microorganisms benefit from this cooperative relationship. What is more, the levels of active drug ingredients inside the cells are reduced, which makes the cells more tolerant to hundreds of antimicrobial substances.”

Fungal infections represent an increasingly significant health issue and are more dangerous than previously thought. Every year, more people worldwide are killed by invasive fungal infections than by malaria.

Further research will evaluate the extent to which microbial tolerance is determined by metabolism and metabolic environment, with the hopes of developing new generations of antifungal drugs.