What is already known on this topic
Every year, fungal infections kill more people than does malaria, as fungal pathogens become less sensitive, or more tolerant, to the only drugs that can treat these infections.
What this research adds
To understand how fungal pathogens develop drug tolerance, researchers analyzed the genetic makeup of more than 12,000 microbial communities from across the globe. They found that microorganisms called auxotrophs, which are unable to produce essential metabolites such as amino acids and vitamins, were present in most communities. Auxotrophs appeared to be cooperative partners in microbial communities, returning metabolites in exchange for essential nutrients, and communities with auxotrophs were more likely to tolerate drugs than communities without them. Further experiments done in yeast suggested that cooperative communities of microbes showed an increased movement of metabolites out of microbial cells, which can result in drugs being removed from cells at higher rates.
Conclusions
The findings could explain why some fungal pathogens are more tolerant to drugs and pave the way to the development of improved antimicrobial therapies.
Every year, fungal infections kill more people than does malaria, as fungal pathogens become less sensitive, or more tolerant, to the only drugs that can treat these infections. Now, researchers have found that cooperation among microbial cells may be one of causes of this drug tolerance.
The findings, published in Nature Microbiology, could pave the way to the development of improved antimicrobial therapies.
“We discovered that yeast cells frequently and actively engage with one another, and that these interactions involve the exchange of metabolites. We were also able to show how this creates both growth advantages and tolerance to common antimycotics,” says study senior author Markus Ralser at the Francis Crick Institute and the Charité University Hospital.
Microbial communities are made of cells that function normally and cells with impaired metabolism, called auxotrophic cells. These cells have lost the ability to produce certain essential metabolites, such as amino acids and vitamins, and must absorb them from other microbial cells present in the environment.
To address whether and how auxotrophic cells benefit from the co-existence with other cells, Ralser and his colleagues analyzed the genetic makeup of more than 12,000 microbial communities from across the globe. The microbial communities were obtained as part of the Earth Microbiome Project, a study of interactions between microbial cells in yeast communities.
Drug tolerance
The researchers found that auxotrophs were present in more than 99% of the communities they studied. Auxotrophs appeared to be cooperative partners in microbial communities, returning metabolites in exchange for essential nutrients.
Auxotrophs were particularly common in microbial communities linked to a host, such as the gut microbiota, the researchers found. Compared to communities without auxotrophs, communities with auxotrophs were more likely to tolerate drugs, especially a specific class of antifungals drugs.
To understand how communities with auxotrophs develop drug tolerance, the researchers turned to laboratory experiments with a yeast model, which allowed them to observe populations of metabolically deficient and metabolically competent cells in isolation.
Cooperative communities
The experiments done in yeast suggested that auxotrophs living in communities with metabolically competent cells adapt their metabolisms to promote the export of metabolites.
The researchers found that cooperative communities of microbes showed an increased movement of metabolites out of microbial cells, which can result in drugs being removed from cells at higher rates.
The findings highlight the complex relationships between microbes within communities, but they may have applications beyond microbial ecology. “[Our observations] open a whole field of research exploring the contribution of metabolism and the metabolic environment to antimicrobial resistance,” Ralser says. “We hope that this will allow the design of new generations of antifungals, that target not only cell growth but also tolerance, and hence will be more effective than the currently available treatments.”
