Explaining how highly resistant strains of fungi emerge

 

Antibiotic resistance is a matter of common knowledge. And the same phenomenon also occurs with drugs against pathogenic fungi. What causes it is still not very well understood.

   

An international research team has deciphered the mechanism by which the fungus Cryptococcus neoformans is resistant to fungus-specific drugs. It is a yeast-like fungus that can infect humans. Specific drugs, named antifungals, are available for treatment, but they don't always work -- a phenomenon similar to antibiotic resistance. A team from Duke University in the USA and Ruhr-Universität Bochum (RUB) has used genetic, bioinformatic and microbiological techniques to decipher the mechanism underlying this resistance.

 

In the western hemisphere, the number of people with a lowered immune defence is increasing, because life expectancies are rising rapidly and treatment with immunosuppressants after organ transplants is becoming more common.

 

Cryptococcus neoformans is one of the most significant human pathogenic fungi responsible for so-called cryptococcosis. It triggers acute infections in immunocompromised patients; and the mortality rate may be as high as 70 per cent. This is because fungal strains that are resistant to the drugs often evolve in hospitals, which makes treatment more difficult. So far, it was unclear which cellular and genetic mechanisms lead to this resistance.

 

 

So-called transposons, however, were known to play a role in the resistances. Transposons are jumping genes, i.e. DNA segments that can change their position in the genome and thus affect the function of genes. If a transposon jumps into a gene that's critical for susceptibility to a drug, it's possible for resistance to emerge. The mobility of the transposons is controlled by regulatory RNAs, so-called small interfering RNA, or siRNA for short.

 

In their current study, the researchers discovered gene mutations in resistant isolates that led to siRNA control being switched off. By introducing an intact copy of the gene, it was possible to restore siRNA control; as a result, the researchers were able to prevent the transposons from jumping and shed light on the cause of resistance. Due to their small size, the gene segments that code for siRNAs are not easy to find in the genome.

 

See:

 

Shelby J. Priest, Vikas Yadav, Cullen Roth, Tim A. Dahlmann, Ulrich Kück, Paul M. Magwene, Joseph Heitman. Uncontrolled transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of Cryptococcus neoformans. Nature Microbiology, 2022; DOI: 10.1038/s41564-022-01183-z

 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)