Researchers from the University of Edinburgh have identified how fungal resistance to drugs develops. Originally, researchers thought that only mutations within the DNA sequence could result in antifungal drug resistance. Now, scientists have discovered that fungi can develop drug resistance without changes to their DNA.
Heterochromatin
Chromatin is a complex of DNA and protein that plays an important role in several cellular processes, including gene expression regulation. Condensed chromatin is known as heterochromatin and is associated with gene silencing as it is inaccessible to polymerases. Specifically, heterochromatin that depends on histone H3 lysine 9 methylation (H3K9me) renders embedded genes transcriptionally silent.
Fungal disease
Each year, fungal disease results in 1.6 million deaths globally. With this, resistant to treatment is a growing problem. This is particularly concerning in patients with weakened immune systems such as HIV patients. Unfortunately, very few effective antifungal drugs exist. Elsewhere, overuse of agricultural fungicides also leads to increasing resistance in soil-borne fungi. As a result, fungal disease results in the loss of up to a third of annual world food crops.
Emergence of resistance
In a study, published in Nature, researchers studied the emergence of resistance in fission yeast – Schizosaccharomyces pombe. The team treated cells with caffeine to mimic the activity of antifungal drugs. They reasoned that if heterochromatin could redistribute in wild-type S. pombe cells, then it should be possible for epimutations to be generated that would enable adaptation to caffeine.
The team found that heterochromatin-dependent epimutations resistant to caffeine arise in fission yeast. Specifically, they found that isolates with unstable resistance had distinct heterochromatin islands with reduced expression of embedded genes. This included some whose mutation conferred caffeine resistance. Researchers also revealed that epigenetic processes promoted phenotype plasticity. In other words, wild-type cells were able to adapt to unfavourable environments without genetic alterations.
These results could pave the way for new therapies that treat infections. Re-engineering existing ‘epigenetic drugs’ (compounds that inhibit histone-modifying enzymes), or searching for other novel agents that inhibit fungal heterochromatin, could help reduce the emergence of antifungal resistance in both clinical and agricultural settings.
Professor Robin Allshire who led the study, stated:
“Our team is excited about the possible implications that these findings may have for understanding how plant, animal and human fungal pathogens develop resistance to the very limited number of available and effective antifungal drug treatments.”
Image credit: By Image Team – canva.com
