Research from the Francis Crick Institute has revealed a key mechanism that increases tolerance to drugs amongst microbial communities. The findings could help the development of more effective antifungal treatments.
Background
Antimicrobial drug resistance and tolerance occurs when bacteria, viruses, fungi or parasites no longer respond, or have less sensitivity, to treatments. It is a major issue within medicine, for example, invasive fungal infections are responsible for 1.6 million deaths annually.
The study
In their study, published in Nature Microbiology, the scientists analysed data from 12,000 microbial communities from all over the world, provided by the Earth Microbiome Project.
Within these groups of different microorganisms, which live together producing and absorbing materials they all need to survive and grow, the researchers found one type in particular was highly prevalent. Auxotrophs, which are unable to create essential metabolites, like amino acids, vitamins or fatty acids, were present in 99.95% of the 12,538 communities they studied.
Findings
By analysing drug exposure data from the project, the scientists found that communities with auxotrophs are more likely to have tolerance against hundreds of drugs, than communities without these cells. Moreover, the research showed that they are not scrounger cells, but rather cooperative partners as, in exchange for taking up metabolites that are essential for them, they return other metabolites to the community.
Further experiments using a yeast model showed that this increased tolerance is because cells that cooperate in metabolism, have increased levels of metabolic export, the movement of metabolites out of cells. As a side-effect, this also causes drugs to be moved out of cells at a higher rate.
Official comments
“Around the world, more people die each year from invasive fungal species than from malaria. There are currently only three classes of antifungal drugs in clinical use and in an increasing number of cases, these antifungals fail. Understanding the mechanisms which increase or decrease the chance of a drug working is crucial to aid the developments of new treatments,” explained Jason Yu, co-first author and postdoctoral training fellow in the Molecular Biology of Metabolism Laboratory at the Crick.
Clara Correia-Melo, co-first author and researcher in the Molecular Biology of Metabolism Laboratory at the Crick and the Department of Biochemistry at University of Cambridge, said: “The widespread nature of auxotrophs has been considered a paradox, a fundamental problem in our understanding of microbiology. This is because they must absorb metabolites from the environment and so they have been thought of as weaker than other cells which can create these chemical compounds themselves. They have been seen as scrounger cells, a drain on communal resources.”
Looking forward
The researchers will continue this work, collecting clinically relevant fungal species and analysing their response to antimicrobials.
