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Importance of RNA modifications in fungal infection resistance could lead to better treatments

An often-overlooked mechanism of gene regulation may be involved in the failure of antifungal drugs in the clinic, claims a German-Austrian research team led by the Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute (Leibniz-HKI). Their study, in Nucleic Acids Research, focused on the mold fungus Aspergillus fumigatus, which can cause life-threatening infections, especially in immunocompromised people.

Identifying changes to the fungal RNA will allow a better understanding of the molecular mechanisms that are responsible for the development of resistance and the fungus' defense mechanisms against drugs.

It's long been known that bacteria are becoming increasingly resistant to antibiotics. Equally critical—although not in the public focus—is the resistance of fungal pathogens to antimycotics, which is exacerbated by the massive use of similar active ingredients in agriculture. This problem is reflected in alarming data: With more than 1 billion infections and about 3.75 million deaths per year, fungal infections are a significant threat to humans—the trend is rising.

The treatment of fungal infections is currently based on a few groups of medically active substances, such as echinocandins, polyenes, azoles or the synthetic molecule fluorocytosine. The team led by Matthew Blango, head of a junior research group at the Leibniz-HKI, used the known mode of action of fluorocytosine on A. fumigatus as the basis for the investigation of the development of fungal resistance.

Ribonucleic acid, or RNA for short, occurs in all living organisms and regulates the storage, transmission and utilization of genetic information, including the production of proteins. A distinction is made between different types of RNA with different functions. For example, tRNA (transfer RNA) is an adapter molecule that deciphers the genetic code on mRNA (messenger RNA) into a functional product (protein) on the ribosome.

RNA research is currently experiencing a small revolution, as numerous control functions of RNA molecules—including those between different organisms—are not yet well known.

All chemical changes to RNA in the cell together form the epitranscriptome, which often serves as a dimmer switch to adjust gene expression. During gene expression, the cell reads the building instructions for a protein from the DNA sequence of a gene and implements them. This enables the cell to function and react to its environment.

This fundamental knowledge of how RNA works helped the researchers to find a precise starting point for studying the role of modifications in fungal biology.

In the study, the research team first examined the enzyme Mod5 in the fungus A. fumigatus. It plays an important role in the modification of tRNA. These chemical changes to the tRNA help the cell to correctly produce proteins that are important for its function.

"In a first step, we removed the Mod5 enzyme from the fungus," reports Alexander Bruch, one of the authors. "As a result, the fungus reacted negatively to stress and switched on a protective system called cross-pathway control at an early stage."

"Normally, this system is activated when the cell is under stress, for example during starvation or the administration of medication," adds his colleague Valentina Lazarova.

"With the protein NmeA, we discovered a new component that is stimulated by this protective system. It helps the fungus to transport harmful substances out of the cell. In this case, allowing the fungus to survive the antifungal agent fluorocytosine," says Bruch.

"We were able to show that proteins such as NmeA help the fungus to evade drug treatment and offer an option to become temporarily resistant to antifungal drugs," says Blango. "Our findings could be used for better treatment strategies against fungal infections. However, we are only at the beginning of research in this area."