Tackling Life-Threatening Fungal Infections Using RNA Modifications

Importance of RNA modifications for the development of resistance in fungi raises hope for more effective treatment of fungal infections.

An often-overlooked mechanism of gene regulation may be involved in the failure of antifungal drugs in the clinic. This has been discovered by a German-Austrian research team led by the Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI). The study focused on the mold fungus 𝘈𝘴𝘱𝘦𝘳𝘨𝘪𝘭𝘭𝘶𝘴 𝘧𝘶𝘮𝘪𝘨𝘢𝘵𝘶𝘴, which can cause life-threatening infections, especially in immunocompromised people. Targeted changes to the fungal RNA allow a better understanding of the molecular mechanisms, which are responsible for the development of resistance and the fungus’ defense mechanisms against drugs.

It’s been long known that bacteria are becoming increasingly resistant to antibiotics. The risk of no longer being able to successfully treat bacterial infections is constantly increasing. 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 over one billion infections and around 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 medical 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.

Great Value Cell Control

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 serve like 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.

Great Value for Money Resistance?

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 to 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. Bruch further explains: “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”.

“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 Matthew 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.”

The study is part of the Jena Cluster of Excellence “Balance of the Microverse”, which researches the regulation and balance of microbial communities, and was funded by the German Research Foundation. Dr. Matthew Blango’s junior research group is funded by the Federal Ministry of Education and Research as part of the “Junior Research Groups in Infection Research” program.

Institutions

1. Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI)
2. Friedrich Schiller University Jena
3. Johann Wolfgang Goethe University Frankfurt am Main
4. Medical University of Innsbruck

Expert Contact
Dr. Matthew Blango
Email ID: matthew.blango@leibniz-hki.de
Phone Number: +49 3641 532-1072

Original Publication
Alexander Bruch, Valentina Lazarova, Maximilian Berg, Thomas Krüger, Sascha Schäuble, Abdulrahman A Kelani, Birte Mertens, Pamela Lehenberger, Olaf Kniemeyer, Stefanie Kaiser, Gianni Panagiotou, Fabio Gsaller, Matthew G Blango
Journal: Nucleic Acids Research
Article Title: tRNA hypomodification facilitates 5-fluorocytosine resistance via cross-pathway control system activation in Aspergillus fumigatus
Article Publication Date: 23 December 2024
DOI: https://doi.org/10.1093/nar/gkae1205

Source: IDW