The importance of RNA modification in fungal infection resistance may lead to better treatments

Written by Maria Schulz, Leibniz Institute for Natural Biology – Hans Kühnel Institute (Leibniz-HKI)
Aspergillus fumigatus colonies plated in the form of transfer RNA molecules. Credit: Matthew Blango, Leibniz-HKI
The failure of antifungal drugs in clinical practice may involve an often-overlooked gene regulatory mechanism, says the Leibniz Research Institute for Natural Products, the Institute for Infection Biology, and the Hans Knell Institute (Leibniz-HKI). ) claims a German-Austrian research team. Their study, published in the journal Nucleic Acids Research, focused on the fungus Aspergillus fumigatus, which can cause life-threatening infections, especially in immunocompromised people.
Identification of changes in fungal RNA will provide a deeper understanding of the molecular mechanisms involved in the development of resistance and the fungal defenses against drugs.
It has long been known that bacteria are becoming increasingly resistant to antibiotics. Equally important, but receiving less attention, is the resistance of fungal pathogens to antifungal drugs, which is further exacerbated by the heavy use of similar active ingredients in agriculture. This problem is reflected in alarming data. Fungal infections are a significant and increasing threat to humans, with over 1 billion infections and approximately 3.75 million deaths annually.
Treatment of fungal infections is currently based on several groups of medically active substances, such as echinocandins, polyenes, azoles, and the synthetic molecule fluorocytosine. The team, led by Leibniz-HKI junior research group leader Matthew Brango, used the known mechanism of action of fluorocytosine on A. fumigatus as the basis for investigating the development of fungal resistance.
Ribonucleic acid (RNA for short) is present in all living organisms and controls the storage, transmission, and use of genetic information, including the production of proteins. Different types of RNA with different functions are distinguished. For example, tRNA (transfer RNA) is an adapter molecule that decodes the genetic code on mRNA (messenger RNA) and converts it into a functional product (protein) on the ribosome.
RNA research is currently undergoing a small revolution, as many regulatory functions of RNA molecules (including those between different organisms) are still poorly understood.
All chemical changes to RNA within a cell come together to form the epitranscriptome. This often acts as a dimmer switch that regulates gene expression. During gene expression, cells read and carry out protein building instructions from the gene’s DNA sequence. This allows cells to function and respond to their environment.
This basic knowledge of how RNA functions has helped researchers find a precise starting point to study the role of modifications in fungal biology.
For the study, the researchers first looked at the enzyme Mod5 from the fungus A. fumigatus. It plays an important role in the modification of tRNA. These chemical changes to tRNA help cells correctly produce proteins that are important for their function.
“As a first step, we removed the Mod5 enzyme from the fungus,” reports Alexander Bruch, one of the authors. “As a result, the fungus responded negatively to stress and early on switched on a defense system called cross-pathway regulation.”
“Normally, this system is activated when cells are under stress, for example during starvation or drug administration,” added colleague Valentina Lazarova.
“With the protein NmeA, we discovered a new component that is stimulated by this protective system. It helps fungi transport harmful substances out of the cell. In this case, the fungus uses the antifungal fluorocytosine ” says Dr. Bruch.
“We were able to show that proteins such as NmeA help fungi evade drug treatment and provide an option for temporary resistance to antifungal drugs,” Brango says. “Our findings could be used for better treatment strategies against fungal infections. However, we are still in the early stages of research in this area.”
Further information: Alexander Bruch et al, tRNA hypomodification promotes 5-fluorocytosine resistance via activation of cross-pathway control systems in Aspergillus fumigatus, Nucleic Acids Research (2024). DOI: 10.1093/nar/gkae1205
Provided by the Leibniz Institute for Natural Biology – Hans Kühnel Institute (Leibniz-HKI)
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